Vitamins and the Immune System [1 ed.] 1865843830, 9780123869609

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Cover photo credit: Hewison, M. Vitamin D and innate and adaptive immunity. Vitamins and Hormones (2011) 86, pp. 23-62. Academic Press is an imprint of Elsevier 32 Jamestown Road, London, NW1 7BY, UK Radarweg 29, PO Box 211, 1000 AE Amsterdam, The Netherlands Linacre House, Jordan Hill, Oxford OX2 8DP, UK 30 Corporate Drive, Suite 400, Burlington, MA 01803, USA 525 B Street, Suite 1900, San Diego, CA 92101-4495, USA First edition 2011 Copyright # 2011 Elsevier Inc. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means electronic, mechanical, photocopying, recording or otherwise without the prior written permission of the publisher Permissions may be sought directly from Elsevier’s Science & Technology Rights Department in Oxford, UK: phone (+44) (0) 1865 843830; fax (+44) (0) 1865 853333; email: [email protected]. Alternatively you can submit your request online by visiting the Elsevier web site at http://elsevier.com/locate/permissions, and selecting Obtaining permission to use Elsevier material Notice No responsibility is assumed by the publisher for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in the material herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made ISBN: 978-0-12-386960-9 ISSN: 0083-6729 For information on all Academic Press publications visit our website at elsevierdirect.com Printed and bound in USA 11 12 13 14 10 9 8 7 6 5 4 3 2 1

Former Editors

ROBERT S. HARRIS

KENNETH V. THIMANN

Newton, Massachusetts

University of California Santa Cruz, California

JOHN A. LORRAINE University of Edinburgh Edinburgh, Scotland

IRA G. WOOL University of Chicago Chicago, Illinois

PAUL L. MUNSON University of North Carolina Chapel Hill, North Carolina

EGON DICZFALUSY Karolinska Sjukhuset Stockholm, Sweden

JOHN GLOVER University of Liverpool Liverpool, England

GERALD D. AURBACH Metabolic Diseases Branch National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health Bethesda, Maryland

ROBERT OLSEN School of Medicine State University of New York at Stony Brook Stony Brook, New York

DONALD B. MCCORMICK Department of Biochemistry Emory University School of Medicine, Atlanta, Georgia

Copyright Pages iv-v Contributors Pages xiii-xvi Preface Pages xvii-xviii Gerald Litwack Chapter one - Vitamin D Regulation of Immune Function Pages 1-21 Daniel D. Bikle Chapter two - Vitamin D and Innate and Adaptive Immunity Pages 23-62 Martin Hewison Chapter three - Dendritic Cells Modified by Vitamin D: Future Immunotherapy for Autoimmune Diseases Pages 63-82 Ayako Wakatsuki Pedersen, Mogens Helweg Claesson, Mai-Britt Zocca Chapter four - Retinoic Acid, Immunity, and Inflammation Pages 83-101 Chang H. Kim Chapter five - Vitamin A and Retinoic Acid in the Regulation of B-Cell Development and Antibody Production Pages 103-126 A. Catharine Ross, Qiuyan Chen, Yifan Ma Chapter Six - Retinoic Acid Production by Intestinal Dendritic Cells Pages 127-152 Makoto Iwata, Aya Yokota Chapter seven - Immune Regulator Vitamin A and T Cell Death Pages 153-178 Nikolai Engedal Chapter eight - Vitamin E and Immunity Pages 179-215 Didem Pekmezci Chapter Nine - Vitamin D Effects on Lung Immunity and Respiratory Diseases Pages 217-237 Sif Hansdottir, Martha M. Monick Chapter Ten - Maternal Vitamin D During Pregnancy and Its Relation to Immune-Mediated Diseases in the Offspring Pages 239-260 M. Erkkola, B.I. Nwaru, H.T. Viljakainen Chapter Eleven - Vitamin D Deficiency and Connective Tissue Disease Pages 261-286 Eva Zold, Zsolt Barta, Edit Bodolay Chapter twelve - Key Roles of Vitamins A, C, and E in Aflatoxin B1-Induced Oxidative Stress Pages 287-305 Lokman Alpsoy, Mehmet Emir Yalvac Chapter thirteen - Vitamin D, Vitamin D Receptor, and Cathelicidin in the Treatment of Tuberculosis Pages 307-325 P. Selvaraj Chapter fourteen - Vitamin D Endocrine System and the Immune Response in Rheumatic Diseases Pages 327-351 Maurizio Cutolo, M. Plebani, Yehuda Shoenfeld, Luciano Adorini, Angela Tincani Chapter fifteen - L-Carnitine and Intestinal Inflammation Pages 353-366 Geneviève Fortin Chapter sixteen - Vitamin D and Inflammatory Bowel Disease Pages 367-377 Sandro Ardizzone, Andrea Cassinotti, Maurizio Bevilacqua, Mario Clerici, Gabriele Bianchi Porro Chapter seventeen - Vitamin D Deficiency and Chronic Obstructive Pulmonary Disease: A Vicious Circle Pages 379-399 Wim Janssens, Chantal Mathieu, Steven Boonen, Marc Decramer Chapter eighteen - Vitamin D as a T-cell Modulator in Multiple Sclerosis Pages 401-428 Joost Smolders, Jan Damoiseaux Chapter Nineteen - Vitamin D in Solid Organ Transplantation with Special Emphasis on Kidney Transplantation Pages 429-468 Ursula Thiem, Kyra Borchhardt Subject Index Pages 469-476

CONTRIBUTORS

Luciano Adorini Intercept Pharmaceuticals, Corciano (Perugia), Italy Lokman Alpsoy Fatih University, Science and Art Faculty, Department of Biology, Buyukcekmece, Istanbul, Turkey Sandro Ardizzone Department of Gastroenterology, “L. Sacco” University Hospital, Milan, Italy Zsolt Barta Division of Clinical Immunology, 3rd Department of Medicine, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary Maurizio Bevilacqua Endocrinology Unit, Department of Clinical Science, “L. Sacco” University Hospital, Milan, Italy Daniel D. Bikle Department of Medicine and Dermatology, Veterans Affairs Medical Center, University of California, San Francisco, California, USA Edit Bodolay Division of Clinical Immunology, 3rd Department of Medicine, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary Steven Boonen Division for Geriatric Medicine and Center of Metabolic Bone Diseases, University of Leuven, Belgium Kyra Borchhardt Division of Nephrology and Dialysis, Department of Internal Medicine III, Medical University of Vienna, Wa¨hringer Gu¨rtel, Vienna, Austria B.I. Nwaru Tampere School of Public Health, University of Tampere, Finland Andrea Cassinotti Department of Gastroenterology, “L. Sacco” University Hospital, Milan, Italy

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Qiuyan Chen Department of Nutritional Sciences, Pennsylvania State University, University Park, Pennsylvania, USA Mogens Helweg Claesson Institute of International Health, Immunology and Microbiology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark Mario Clerici Chair of Immunology, DISP LITA Vialba, and DISTeB LITA Segrate, University of Milan, Milan, Italy Maurizio Cutolo Rheumatology, Research Laboratories and Academic Unit of Clinical Rheumatology, Postgraduate Academic School of Rheumatology, University of Genova, Genova, Italy Jan Damoiseaux Laboratory of Clinical Immunology, Maastricht University Medical Center, Maastricht, The Netherlands Marc Decramer Respiratory Division, University of Leuven, Herestraat 49, Leuven, Belgium Nikolai Engedal Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, Oslo, Norway Genevie`ve Fortin Department of Experimental Medicine, McGill University, Montreal, Quebec, Canada Sif Hansdottir Department of Medicine, University of Iowa Carver College of Medicine and Veterans Administration Medical Center, Iowa City, Iowa, USA H.T. Viljakainen Hospital for Children and Adolescents, HUS, Finland Martin Hewison Department of Orthopaedic Surgery and Molecular Biology Institute, David Geffen School of Medicine at UCLA, Los Angeles, California, USA Makoto Iwata Laboratory of Immunology, Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, Sanuki-shi, Kagawa, Japan, and Japan Science and Technology Agency, CREST, Chiyoda-ku, Tokyo, Japan Wim Janssens Respiratory Division, University of Leuven, Herestraat 49, Leuven, Belgium

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Chang H. Kim Laboratory of Immunology and Hematopoiesis, Department of Comparative Pathobiology, School of Veterinary Medicine and Center for Cancer Research, Purdue University, West Lafayette, Indiana, USA Yifan Ma Department of Nutritional Sciences, Pennsylvania State University, University Park, Pennsylvania, USA M. Erkkola Division of Nutrition, Department of Food and Environmental Sciences, University of Helsinki, Finland Chantal Mathieu Division of Endocrinology, University of Leuven, Belgium Martha M. Monick Department of Medicine, University of Iowa Carver College of Medicine and Veterans Administration Medical Center, Iowa City, Iowa, USA Ayako Wakatsuki Pedersen DanDrit Biotech A/S, Symbion Science Park, Copenhagen, Denmark Didem Pekmezci Department of Internal Medicine, Faculty of Veterinary Medicine, University of Ondokuz Mayıs, Kurupelit, Samsun, Turkey M. Plebani Department of Laboratory Medicine, University Hospital of Padova, Padova, Italy Gabriele Bianchi Porro Department of Gastroenterology, “L. Sacco” University Hospital, Milan, Italy A. Catharine Ross Department of Nutritional Sciences, and Huck Institute for Life Sciences, Pennsylvania State University, University Park, Pennsylvania, USA P. Selvaraj Department of Immunology, Tuberculosis Research Centre, Indian Council of Medical Research, Chennai, India Yehuda Shoenfeld Department of Medicine ‘B’, Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center (Affiliated to Tel-Aviv University), Tel-Hashomer, Israel, and Incumbent of the Laura Schwarz-Kipp Chair for Research of Autoimmune Diseases, Tel-Aviv University, Tel-Aviv, Israel

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Joost Smolders School for Mental Health and Neuroscience, and Department of Internal Medicine, Division of Clinical and Experimental Immunology, Maastricht University Medical Center, Maastricht, The Netherlands Ursula Thiem Division of Nephrology and Dialysis, Department of Internal Medicine III, Medical University of Vienna, Wa¨hringer Gu¨rtel, Vienna, Austria Angela Tincani Rheumatology and Clinical Immunology, Spedali Civili and University of Brescia, Brescia, Italy Mehmet Emir Yalvac Yeditepe University, Faculty of Engineering and Architecture, Department of Genetics and Bioengineering, Istanbul, Turkey Aya Yokota Laboratory of Immunology, Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, Sanuki-shi, Kagawa, Japan, and Japan Science and Technology Agency, CREST, Chiyoda-ku, Tokyo, Japan Mai-Britt Zocca DanDrit Biotech A/S, Symbion Science Park, Copenhagen, Denmark Eva Zold Division of Clinical Immunology, 3rd Department of Medicine, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary

PREFACE

The relationship of vitamin intake to the functioning of the immune system has been emphasized in recent times. A prime example is the linkage between vitamin D deficiency and the genesis of colon cancer. It is now known that there are many such linkages between vitamin deficiencies and various disease conditions. Much of these phenomena can be related to the effects of vitamins on the functionality of the immune system, the system by which beginning cancers are removed. In this volume is reviewed the recent knowledge of these relationships involving vitamin D, vitamin A, vitamin E, vitamin C, and even L-carnitine which, itself, is not classified as a vitamin but has interesting effects on immunity and inflammation. I have tried to arrange the contributions so that more general discussions appear at first and more specific discussions about individual disease conditions are presented afterward. Accordingly, the first chapter is entitled “Vitamin D Regulation of Immune Function” by D. D. Bikle. This is followed by “Vitamin D and Innate and Adaptive Immunity” by M. Hewison. This is followed by “Dendritic Cells Modified by Vitamin D: Future Immunotherapy for Autoimmune Diseases” by A. W. Pedersen, M. H. Claesson, and M.-B. Zocca. C. H. Kim reviews “Retinoic Acid, Immunity, and Inflammation.” A. C. Ross, Q. Chen, and Y. Ma follow with “Vitamin A and Retinoic Acid in the Regulation of B Cell Development and Antibody Production.” Retinoic acid is also the topic of M. Iwata and A. Yokota who introduce “Retinoic Acid Production by Intestinal Dendritic Cells.” N. Engedal reviews “Immune Regulator Vitamin A and T Cell Death.” Vitamin E comes into the picture with “Vitamin E and Immunity” by D. Pekmezci, and this completes the general topics. Relating to more specific diseases, S. Hansdottir and M. M. Monick offer “Vitamin D Effects on Lung Immunity and Respiratory Diseases.” “Maternal Vitamin D During Pregnancy and Its Relation to Immune-Mediated Diseases in the Offspring” is the subject of E. Maijaliisa, N. Bright I, and H. T. Viljakainen. “Vitamin D Deficiency and Connective Tissue Disease” is by E. Zold, Z. Barta, and E. Bodolay. L. Alpsoy and M. E. Yalvac introduce “Key Roles of Vitamin A, C, and E in Aflatoxin B1-Induced Oxidative Stress.” “Vitamin D, Vitamin D Receptor, and Cathelicidin in the Treatment of Tuberculosis” is the contribution of P. Selvaraj. M. Cutolo, M. Plebani, Y. Shoenfeld, L. Adorini, and A. Tincani write about “Vitamin D Endocrine System and the Immune Response in Rheumatic Diseases.” G. Fortin introduces “L-Carnitine and Intestinal xvii

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Inflammation.” Bowel disease is discussed by S. Ardizzone, A. Cassinotti, M. Bevilacqua, M. Clerici, and G. B. Porro. W. Janssens, C. Mathieu, S. Boonen, and M. Decramer describe “Vitamin D Deficiency and Chronic Obstructive Pulmonary Disease: A Vicious Circle.” J. Smolders and J. Damoiseaux introduce “Vitamin D as a T Cell Modulator in Multiple Sclerosis.” Finally, U. Thiem and K. Borchhardt detail “Vitamin D in Solid Organ Transplantation with Special Emphasis on Kidney Transplantation.” Key roles in the final processing of this volume have been played by Delsy Retchagar with oversight by Lisa Tickner and lately by Mary Ann Zimmerman and others at Elsevier. The cover figure is reproduced from Figure 2.2 from the contribution entitled "Vitamin D and innate and adaptive immunity" by Martin Hewison. Gerald Litwack Scranton, PA

C H A P T E R

O N E

Vitamin D Regulation of Immune Function Daniel D. Bikle

Contents I. Introduction II. 1,25(OH)2D Production in Cells of the Immune System: Comparisons to Renal Production III. Role of Vitamin D in the Adaptive Immune Response (Fig. 1.2) IV. Clinical Implications of the Inhibition of the Adaptive Immune Response A. Inhibition by vitamin D of autoimmunity B. Vitamin D protection of tissue transplants C. Vitamin D inhibition of adaptive immunity may have adverse effects V. Role of Vitamin D in the Innate Immune Response (Fig. 1.3) A. Macrophages B. Keratinocytes C. Vitamin D stimulation of the innate immune response may have adverse effects VI. Conclusion Acknowledgments References

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Abstract Although the best known actions of vitamin D involve its regulation of bone mineral homeostasis, vitamin D exerts its influence on many physiologic processes. One of these processes is the immune system. Both the adaptive and innate immune systems are impacted by the active metabolite of vitamin D, 1,25 (OH)2D. These observations have important implications for understanding the predisposition of individuals with vitamin D deficiency to infectious diseases such as tuberculosis as well as to autoimmune diseases such as type 1 diabetes mellitus and multiple sclerosis. However, depending on the disease process not all actions of vitamin D may be beneficial. In this review, I examine the Department of Medicine and Dermatology, Veterans Affairs Medical Center, University of California, San Francisco, California, USA Vitamins and Hormones, Volume 86 ISSN 0083-6729, DOI: 10.1016/B978-0-12-386960-9.00001-0

#

2011 Elsevier Inc. All rights reserved.

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regulation by 1,25(OH)2D of immune function, then assess the evidence implicating vitamin D deficiency in human disease resulting from immune dysfunction. ß 2011 Elsevier Inc.

I. Introduction The potential role for vitamin D and its active metabolite 1,25(OH)2D in modulating the immune response has long been recognized since the discovery of vitamin D receptors (VDRs) in macrophages, dendritic cells (DCs), and activated T and B lymphocytes, the ability of macrophages and DCs as well as activated T and B cells to express CYP27B1, the enzyme that produces 1,25(OH)2D, and the ability of 1,25(OH)2D to regulate the proliferation and function of these cells. While these are the key cells mediating the adaptive immune response, 1,25(OH)2D, VDR, and CYP27B1 are also expressed in a large number of epithelial cells which along with the aforementioned members of the “professional” immune system contribute to host defense by their innate immune response. The totality of the immune response involves both types of responses in complex interactions involving numerous cytokines. The regulation by 1,25(OH)2D of these different responses and their interactions is nuanced. In general, 1,25(OH)2D enhances the innate immune response primarily via its ability to stimulate cathelicidin, an antimicrobial peptide (AMP) important in defense against invading organisms, whereas it inhibits the adaptive immune response primarily by inhibiting the maturation of DCs important for antigen presentation, reducing T cell proliferation, and shifting the balance of T cell differentiation from the Th1 and Th17 pathways to Th2 and regulatory T cells (Treg) pathways. Impairment of the innate immune system in vitamin D deficiency predisposes to tuberculosis, whereas an overactive adaptive immune system in vitamin D deficiency may account for the higher incidence of type 1 diabetes mellitus in children born to vitamin D deficient mothers or the increased incidence of multiple sclerosis in young adults.

II. 1,25(OH)2D Production in Cells of the Immune System: Comparisons to Renal Production Before reviewing the regulation by 1,25(OH)2D of immune function, the importance of the ability of cells involved with the immune response to produce their own 1,25(OH)2D needs to be emphasized. 1,25(OH)2D is produced from 25OHD by the enzyme 25OHD-1a-hydroxylase (CYP27B1). Mutations in this gene are responsible for the rare autosomal

A

Osteocyte

+

25 OHD

Kidney

FGF23 PTH −

CYP27b1 −

−

Parathyroid glands

+

1,25(OH)2D

B SUN

7-DHC + D3 +

25OHD3 +

1,25(OH)2D3

24,25(OH)2D3 +

+ 1,24,25(OH)3D3

IFN-g

TLR2

TNF-a

Figure 1.1 Comparison of the regulation of CYP27B1 in the kidney with that in the keratinocyte. (A) CYP27B1 in the kidney is regulated principally by three hormones: PTH, FGF23, and its product 1,25(OH)2D. PTH stimulates, while FGF23 and 1,25(OH)2D inhibit CYP27B1. 1,25(OH)2D in turn inhibits PTH production while stimulating that of FGF23. Calcium and phosphate likewise regulate PTH and FGF23 production, providing feedback loops that tightly control CYP27B1 activity and maintain normal calcium and phosphate homeostasis. Adapted from Figure 2 in Bikle (2009). (B) In the keratinocyte and other extrarenal sites of CYP27B1 expression, 1,25(OH)2D3 production is controlled primarily by cytokines such as IFN-g and TNF-a and activation of toll-like receptors (TLRs). Unlike the kidney, 1,25(OH)2D3 regulates its own levels within the cell primarily by induction of CYP24, which catabolizes both the substrate (25OHD3) and product (1,25(OH)2D3) of CYP27B1. In the macrophage, this latter mechanism is lax, and conditions of increased macrophage activation can lead to excess 1,25(OH)2D3 production and hypercalcemia.

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disease of pseudovitamin D deficiency (Fu et al., 1997; Kitanaka et al., 1998; St-Arnaud et al., 1997; Wang et al., 1998). An animal model in which the gene is knocked out by homologous recombination reproduces the clinical features of this disease including retarded growth, rickets, hypocalcemia, hyperparathyroidism, and undetectable 1,25(OH)2D (Dardenne et al., 2001), although the immune system has received little study in this model so far. CYP27B1 is a mitochondrial mixed function oxidase with significant homology to other mitochondrial steroid hydroxylases. These mitochondrial P450 enzymes are located in the inner membrane of the mitochondrion, and serve as the terminal acceptor for electrons transferred from NADPH through ferrodoxin reductase and ferrodoxin. Expression of CYP27B1 is highest in epidermal keratinocytes (Fu et al., 1997; Liu et al., 2007a), but it is well expressed in the epithelium of other organs including the prostate, lungs, intestine, and breast (Bikle, 2010) as well as macrophages, DCs, T, and B lymphocytes (Chen et al., 2007; Sigmundsdottir et al., 2007), but only when these cells are activated. However, the kidney is the major source of circulating 1,25(OH)2D. The principal regulators of CYP27B1 activity in the kidney are parathyroid hormone (PTH), FGF23, calcium, phosphate, and 1,25(OH)2D itself. Extrarenal production tends to be stimulated by cytokines such as interferon-g (IFN-g) and tumor necrosis factor-a (TNF-a) more effectively than PTH (Bikle and Pillai, 1993), as these cells are not known to express the PTH receptor, and may be less inhibited by calcium, phosphate, and 1,25(OH)2D depending on the tissue. Only cells expressing both the FGF receptor and Klotho respond to FGF23; the presence of these coreceptors has not been evaluated in cells of the immune system. Administration of PTH in vivo (Horiuchi et al., 1977) or in vitro (Rasmussen et al., 1972; Rost et al., 1981) stimulates renal production of 1,25(OH)2D. This action of PTH can be mimicked by cAMP (Horiuchi et al., 1977; Rost et al., 1981) and forskolin (Armbrecht et al., 1984; Henry, 1985) indicating that at least part of the effect of PTH is mediated via its activation of adenylate cyclase. However, PTH activation of protein kinase C (PKC) also appears to be involved ( Janulis et al., 1992, 1993). Calcium suppresses CYP27B1 directly and indirectly by inhibiting PTH secretion. FGF23 inhibits CYP27B1 activity in vivo and in vitro and impairs phosphate reabsorption in the kidney (Saito et al., 2003). FGF23 has been implicated as at least one of the factors responsible for impaired phosphate reabsorption and 1,25 (OH)2D production in conditions such as X-linked and autosomal dominant hypophosphatemic rickets and oncogenic osteomalacia (Shimada et al., 2001; White et al., 2000). The immune function in these individuals has received little attention. 1,25(OH)2D administration leads to an apparent reduction in CYP27B1 activity. It was initially thought that this feedback inhibition was mediated at the level of gene expression. However, no vitamin D response element (VDRE) has been identified in the promoter

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of the 1a-hydroxylase gene (Brenza et al., 1998). In keratinocytes, 1,25 (OH)2D has little or no effect on CYP27B1 mRNA and protein levels when given in vitro. When 24-hydroxylase activity (the major catabolic pathway for 1,25(OH)2D) is blocked, 1,25(OH)2D administration fails to reduce the levels of 1,25(OH)2D produced (Schuster et al., 2001; Xie et al., 2001). Thus the apparent feedback regulation of CYP27B1 activity by 1,25 (OH)2D appears to be due to its stimulation of CYP24A1 (24-hydroxylase) and subsequent catabolism, not to a direct effect on CYP27B1 expression or activity at least in keratinocytes. However, in one renal cell line, a chromatin remodeling complex (WINAC) has been described that mediates the ability of the VDR to regulate CYP27B1 gene expression in a nonclassic manner enabling 1,25(OH)2D suppression of this gene (Kato et al., 2007); whether this mechanism is operative in other cells including normal kidney or immune cells remains to be demonstrated. For most cells, the substrate for CYP27B1, 25OHD, is produced from vitamin D by the liver. 25OHD is the major circulating form of vitamin D and provides a clinically useful marker for vitamin D status. 25-Hydroxylase activity has been found in both the liver mitochondria and endoplasmic reticulum, and the enzymatic activities differ, indicating different proteins. Indeed, the mitochondrial 25-hydroxylase is CYP27A1 and the major microsomal 25-hydroxylase is CYP2R1. However, in mouse knockout studies and in humans with mutations in these enzymes, only CYP2R1 loss is clearly associated with changes in vitamin D metabolite production. These are mixed function oxidases, but differ in apparent Kms and substrate specificities. The mitochondrial CYP27A1 was first identified as catalyzing a critical step in the bile acid synthesis pathway. This is a high capacity, low affinity enzyme consistent with the observation that 25-hydroxylation is not generally rate limiting in vitamin D metabolism (Andersson et al., 1989; Cali and Russell, 1991; Usui et al., 1990). CYP27A1 is widely distributed throughout different tissues with highest levels not only in liver and muscle but also in kidney, intestine, lung, skin, bone, and some immune cells (Andersson et al., 1989; Cali and Russell, 1991; Cali et al., 1991; Ichikawa et al., 1995; Leitersdorf et al., 1993; Usui et al., 1990). Mutations in CYP27A1 lead to cerebrotendinous xanthomatosis (Cali et al., 1991; Leitersdorf et al., 1993), and is associated with abnormal vitamin D and/or calcium metabolism in some but not all of these patients (Berginer et al., 1993; Leitersdorf et al., 1993, 1994). CYP2R1, like that of CYP27A1, is widely distributed, although it is most abundantly expressed in liver, skin, and testes (Cheng et al., 2003). The skin expresses less and the testes lack CYP27A1 expression (Cheng et al., 2003). Unlike CYP27A1, CYP2R1 25-hydroxylates D2 and D3 equally (Cheng et al., 2003). A patient with an inactivating mutation in CYP2R1 has been described with rickets and reduced 25OHD levels, reduced serum calcium and phosphate, but normal 1,25(OH)2D levels (Cheng et al., 2004). No comment was made regarding

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immune deficiencies in this patient. The subject responded to D2 therapy (Cheng et al., 2004). Thus CYP27A1 and CYP2R1 by themselves do not account for all 25-hydroxyase activity in the body, but each most likely contributes and together may account for most if not all of the 25-hydroxylase activity in humans. Keratinocytes, DCs but not T cells also express CYP27A1, and both DCs and T cells express CYP2R1 (Lehmann et al., 2004; Sigmundsdottir et al., 2007). However, only DCs produce 1,25(OH)2D from vitamin D3, suggesting that the CYP2R1 is not functional in the T cells (Sigmundsdottir et al., 2007). Furthermore, CYP24A1 expression and activity, the 1,25 (OH)2D-inducible enzyme that catabolizes 25OHD and 1,25(OH)2D, in activated macrophages and DCs is either absent (Sigmundsdottir et al., 2007) or blocked (Ren et al., 2005; Vidal et al., 2002), removing this feedback control of the 1,25(OH)2D produced. Diseases associated with immune activation can and do lead to hypercalcemia and hypercalciuria as a result of increased circulating levels of 1,25(OH)2D (reviewed in Bikle, 2010). The mechanisms for this lack of feedback control are several. First, the major drivers for CYP27B1 expression and activity in these cells are cytokines, not PTH, and cytokines are not regulated by calcium and phosphate. Second, CYP24A1 induction and/or function in macrophages in response to 1,25 (OH)2D is blunted. One mechanism appears to involve the expression of a truncated form of CYP24A1, which includes the substrate binding domain but not the mitochondrial targeting sequence. This truncated form is postulated to act as a dominant negative form of CYP24A1, binding 1,25 (OH)2D within the cytoplasm and preventing its catabolism (Ren et al., 2005). A second mechanism involves the ability of STAT-1 (induced by IFN-g) to complex with VDR blocking its ability to bind to and activate the VDRE in the CYP24A1 promoter (Vidal et al., 2002). As noted above, epithelia are key players in the initiation of the innate immune response, the first line of defense to invading microorganisms, and CYP27B1 expression and activity have been found in most epithelia where they have been sought (Bikle, 2010). Epidermal keratinocytes also express CYP27A1 enabling them to produce 1,25(OH)2D from endogenous sources of vitamin D3 (Lehmann et al., 2004). Ultraviolet B (UVB) radiation, which increases vitamin D and subsequently 1,25(OH)2D production in epidermal keratinocytes, suppresses the adaptive immune response mediating contact hypersensitivity (Loser et al., 2006), while increasing the innate immune response (Zasloff, 2005). Suppression of the adaptive immune response is at least partially attributable to 1,25(OH)2D-induced expression of RANKL in keratinocytes leading to activation of Langerhans cells, and the subsequent induction of Treg (Loser et al., 2006). Activation of the innate immune response is due to 1,25(OH)2D induced cathelicidin production (Zasloff, 2005). Unlike macrophages, these epithelia also express CYP24A1, which limits the levels of 1,25(OH)2D within these tissues such

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that the 1,25(OH)2D produced is likely to play primarily a paracrine or an autocrine role in these tissues and not lead to systemic effects on calcium metabolism. Regulation of CYP27B1 in these cells differs from that of the kidney (Fig. 1.1). Pulmonary alveolar macrophage production of 1,25(OH)2D requires activation by IFN-g and TNF-a, and is inhibited by dexamethasone (Pryke et al., 1990). The production of 1,25(OH)2D by circulating monocytes can be stimulated by IFN-g and other cytokines including TNF-a, interleukin (IL)-1 and IL-2 (Gyetko et al., 1993). Lipopolysaccharide (LPS) has also been shown to induce CYP27B1 (Stoffels et al., 2006). LPS stimulates through specific toll-like receptors (TLRs) in association with the coreceptor CD14, an important trigger of the innate immune response. Such stimulation involves signaling through the JAK/STAT, p38 MAPK, and nuclear factor (NF)-kB pathways, and implicates CEBPb as a key transcription factor (Stoffels et al., 2006). Like the macrophage, TNF (Bikle et al., 1991) and IFN (Bikle et al., 1989) are potent inducers of CYP27B1 activity in the keratinocyte. In pulmonary epithelial cells, double-stranded RNA (poly I:C) and the RSV virus, also ligands for specific TLRs, induce CYP27B1 (Hansdottir et al., 2008), again illustrating the importance of the innate immune response in activating 1,25(OH)2D production.

III. Role of Vitamin D in the Adaptive Immune Response (Fig. 1.2) The adaptive immune response is initiated by cells specialized in antigen presentation, DCs and macrophages in particular, activating the cells responsible for subsequent antigen recognition, T and B lymphocytes. These cells are capable of a wide repertoire of responses that ultimately determine the nature and duration of the immune response. Activation of T and B cells occurs after a priming period in tissues of the body, for example, lymph nodes, distant from the site of the initial exposure to the antigenic substance, and is marked by proliferation of the activated T and B cells accompanied by posttranslational modifications of immunoglobulin production that enable the cellular response to adapt specifically to the antigen presented. Importantly, the type of T cell activated, CD4 or CD8, or within the helper T cell class Th1, Th2, Th17, Treg, and subtle variations of those, is dependent on the context of the antigen presented by which cell and in what environment. Systemic factors such as vitamin D influence this process. Vitamin D in general exerts an inhibitory action on the adaptive immune system. 1,25(OH)2D decreases the maturation of DCs as marked by inhibited expression of the costimulatory molecules HLA-DR, CD40,

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Adaptive immunity

Dendritic cell

25OHD

Treg

CD4

−

−

+

+ −

Th1

Th2

Th17

CYP27B1 1,25(OH)2D Macrophage

Figure 1.2 1,25(OH)2D regulates adaptive immunity. CYP27B1 activity in either the macrophage or the keratinocyte is increased by cytokines. The 1,25(OH)2D produced then serves to inhibit the adaptive response by suppressing Th1 and Th17 proliferation and function while promoting Th2 and Treg functions. Adapted from Figure 3 in Bikle (2009).

CD80, and CD86, decreasing their ability to present antigen and so activate T cells (van Etten and Mathieu, 2005). Furthermore, by suppressing IL-12 production, important for Th1 development, and IL-23 and IL-6 production, important for Th17 development and function, 1,25(OH)2D inhibits the development of Th1 cells capable of producing IFN-g and IL-2 and of Th17 cells producing IL-17 (Daniel et al., 2008). These actions prevent further antigen presentation to and recruitment of T lymphocytes (role of IFN-g), and T lymphocyte proliferation (role of IL-2). Furthermore, suppression of IL-12 increases the development of Th2 cells leading to increased IL-4, IL-5, and IL-13 production, which further suppresses Th1 development shifting the balance to a Th2 cell phenotype. Treatment of DCs with 1,25(OH)2D can also induce CD4þ/CD25þ regulatory T cells (Treg) (Gregori et al., 2001) as shown by increased FoxP3 expression, critical for Treg development (Daniel et al., 2008). These cells produce IL-10, which suppresses the development of the other Th subclasses. Treg are critical for the induction of immune tolerance (Sakaguchi et al., 2008). In addition, 1,25(OH)2D alters the homing properties of T cells, for example, by inducing expression of CCR10, the receptor for CCL27, a keratinocyte specific cytokine, while suppressing that of CCR9, a gut homing receptor (Sigmundsdottir et al., 2007). The actions of 1,25

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(OH)2D on B cells have received less attention, but recent studies have demonstrated a reduction in proliferation, maturation to plasma cells and immunoglobulin production (Chen et al., 2007). 1,25(OH)2D has both direct and indirect effects on regulation of a number of cytokines involved with the immune response (reviewed in Bouillon et al., 2008). TNF has a VDRE in its promoter to which the VDR/retinoid X receptor (RXR) complex binds. 1,25(OH)2D both blocks the activation of NF-kB via an increase in IkBa expression and impedes its binding to its response elements in the genes such as IL-8 and IL-12 that it regulates. 1,25(OH)2D has also been shown to bring an inhibitor complex containing histone deacetylase 3 (HDAC3) to the promoter of rel B, one of the members of the NF-kB family, thus suppressing gene expression. Thus, TNF/NF-kB activity is markedly impaired by 1,25 (OH)2D at multiple levels. In VDR null fibroblasts, NF-kB activity is enhanced. Furthermore, 1,25(OH)2D suppresses IFN-g and a negative VDRE has been found in the IFN-g promoter. Granulocyte/macrophage colony-stimulating factor (GM-CSF) is regulated by VDR monomers binding to a repressive complex in the promoter of this gene, competing with nuclear factor of T cells 1 (NFAT1) for binding to the promoter.

IV. Clinical Implications of the Inhibition of the Adaptive Immune Response A. Inhibition by vitamin D of autoimmunity The ability of 1,25(OH)2D to suppress the adaptive immune system appears to be beneficial for a number of conditions in which the immune system is directed at self, that is, autoimmunity (reviewed in Adorini and Penna, 2008). In a number of experimental models including inflammatory arthritis, psoriasis, autoimmune diabetes (e.g., NOD mice), systemic lupus erythematosus (SLE), experimental allergic encephalitis (EAE) (a model for multiple sclerosis), inflammatory bowel disease (IBD), prostatitis, and thyroiditis, VDR agonist administration has prevented and/or treated the disease process. These actions of 1,25(OH)2D were originally ascribed to inhibition of Th1 function, but Th17 cells have recently been shown to play important roles in a number of these conditions including psoriasis (Adamopoulos and Bowman, 2008), experimental colitis (Daniel et al., 2008), and rheumatoid arthritis (Adamopoulos and Bowman, 2008), conditions that respond to 1,25(OH)2D and its analogs. Although few prospective, randomized, placebo controlled trials in humans have been performed, epidemiologic and case-control studies indicate that a number of these diseases in humans are favorably impacted by adequate vitamin D levels.

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For example, the incidence of multiple sclerosis correlates inversely with 25OHD levels and vitamin D intake (Ascherio et al., 2010), and early studies suggested benefit in the treatment of patients with rheumatoid arthritis and multiple sclerosis with VDR agonists (Adorini and Penna, 2008; Bouillon et al., 2008). Children who are vitamin D deficient have a higher risk of developing type 1 diabetes mellitus, and supplementation with vitamin D during early childhood and/or of mothers during pregnancy may reduce the risk of developing type 1 diabetes (Knip et al., 2010; van Etten and Mathieu, 2005). In VDR null mice, myelopoiesis and the composition of lymphoid organs are normal, although a number of abnormalities in the immune response have been found. Some of the abnormalities in macrophage function and T cell proliferation in response to anti-CD3 stimulation in these animals could be reversed by placing the animals on a high calcium diet to normalize serum calcium (Mathieu et al., 2001). These results indicate the important role of calcium in vitamin D-regulated immune function as in skeletal development and maintenance, an area that has received limited investigation. Other studies have noted an increased number of mature DCs in the lymph nodes of VDR null mice, which would be expected to promote the adaptive immune response (O’Kelly et al., 2002). Somewhat surprisingly, RANKL also increases the number and retention of DCs in lymph nodes ( Josien et al., 2000), suggesting that at least this mechanism is not mediated via the RANKL/RANK system in VDR null mice, which would be expected to reduce RANKL signaling. In contrast to these inhibitory actions of 1,25(OH)2D, Th2 function, as indicated by increased IgE stimulated histamine from mast cells, is increased in VDR null mice (Baroni et al., 2007). The IL-10 null mouse model of IBD shows an accelerated disease profile when bred with the VDR null mouse with increased expression of Th1 cytokines (Froicu et al., 2003). Surprisingly, despite a reduction in natural killer T cells and Treg and a decreased number of mature DCs, VDR null mice bred with NOD mice do not show accelerated development of diabetes (Gysemans et al., 2008). Part of the difference in tissue response in VDR null mice may relate to differences in the ability of 1,25(OH)2D to alter the homing of T cells to the different tissues (Sigmundsdottir et al., 2007).

B. Vitamin D protection of tissue transplants Inhibition of the adaptive immune response may also have benefit in transplantation procedures (Adorini, 2005). In experimental allograft models of the aorta, bone, bone marrow, heart, kidney, liver, pancreatic islets, skin, and small bowel, VDR agonists have shown benefit generally in combination with other immunosuppressive agents such as cyclosporine, tacrolimus, sirolimus, and glucocorticoids (Adorini, 2005). Much of the

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effect could be attributed to a reduction in infiltration of Th1 cells, macrophages, and DCs into the grafted tissue associated with a reduction in chemokines such as CXCL10, CXCL9, CCL2, and CCL5. CXCL10, the ligand for CXCR3, may be of particular importance for acute rejection in a number of tissues, whereas CXCL9 as well as CXCL10 (both CXCR3 ligands) may be more important for chronic rejection at least in the heart and kidney, respectively. A recent report noted that vitamin D supplementation to individuals following liver transplantation to prevent osteoporosis was associated with fewer episodes of acute rejection (Bitetto et al., 2010). However, the results of large-scale prospective randomized control trials have not been reported.

C. Vitamin D inhibition of adaptive immunity may have adverse effects Suppression of the adaptive immune system may not be without a price. Several publications have demonstrated that for some infections including Leishmania major (Ehrchen et al., 2007) and toxoplasmosis (Rajapakse et al., 2005), 1,25(OH)2D promotes the infection (Rajapakse et al., 2005), while the mouse null for VDR is protected (Ehrchen et al., 2007). This may be due at least in part to the loss of IFN-g stimulation of reactive oxygen species (ROS) and nitric oxide (NO) production required for macrophage antimicrobial activity (Ehrchen et al., 2007). In allergic airway disease (asthma), Th2 cells, not Th1 cells, dominate the inflammatory response. 1,25(OH)2D administration to normal mice protected these mice from experimentally induced asthma in one study, blocking eosinophil infiltration, IL-4 production, and limiting histologic evidence of inflammation (Topilski et al., 2004). Furthermore, in humans, vitamin D deficiency is associated with increased risk of severe asthmatic exacerbations (Brehm et al., 2010). However, a study with VDR null mice using a comparable method of inducing asthma showed that lack of VDR also protected the mice from an inflammatory response in their lungs (Wittke et al., 2004). Furthermore, atopic dermatitis, a disease associated with increased Th2 activity (Soumelis et al., 2002), and allergic airway disease, likewise associated with increased Th2 activity, (Topilski et al., 2004; Wittke et al., 2004, 2007), may be aggravated by 1,25(OH)2D and less severe in animals null for VDR. These concerns are supported by one small clinical study in which higher vitamin D intake during infancy was associated with increased incidence of atopic allergies (Back et al., 2009). These results will need confirmation in larger randomized placebo controlled prospective trials. However, at this point, the role of vitamin D in allergic diseases in humans remains unclear, with evidence for both benefit and harm.

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V. Role of Vitamin D in the Innate Immune Response (Fig. 1.3) The innate immune response involves the activation of TLRs in polymorphonuclear cells (PMNs), monocytes, and macrophages as well as in a number of epithelial cells including those of the epidermis, gingiva, intestine, vagina, bladder, and lungs (reviewed in Liu et al., 2007a). There are 10 functional TLRs in human cells (of 11 known mammalian TLRs). TLRs are an extended family of host noncatalytic transmembrane pathogen-recognition receptors that interact with specific membrane patterns (PAMP) shed by infectious agents that trigger the innate immune response in the host. A number of these TLRs signal through adapter molecules such as myeloid differentiation factor-88 (MyD88) and the TIR-domain containing adapter inducing IFN-b (TRIF). MyD88 signaling includes translocation of NF-kB to the nucleus, leading to the production and secretion of a number of inflammatory cytokines. TRIF signaling leads to the activation of interferon regulatory factor-3 (IRF-3) and the induction of type 1 interferons such as IFN-b. MyD88 mediates signaling from TLR 2, 4, 5, 7,

Innate immunity lipo

pep

tide TLR

25OHD

+ +

CYP27B1 VDR

+

cathelicidin

1,25(OH)2D

Macrophage or Keratinocyte

Figure 1.3 1,25(OH)2D regulates innate immunity. CYP27B1 and the VDR in either the macrophage or the keratinocyte are induced by activation of TLR by foreign proteins such as the lipopeptide of M. tuberculosis. The 1,25(OH)2D produced from either endogenous or exogenous 25OHD promotes innate immunity by increasing cathelicidin expression, which kills the invading microorganism. Adapted from Figure 3 in Bikle (2009).

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and 9, whereas TRIF mediates signaling from TLR 3 and 4. TLR1/2, TLR4, TLR5, and TLR2/6 respond to bacterial ligands, whereas TLR3, TLR7, and TLR 8 respond to viral ligands. The TLR response to fungi is less well defined. CD14 serves as a coreceptor for a number of these TLRs. Activation of TLRs leads to the induction of AMPs and ROS, which kill the organism. Among those AMPs is cathelicidin. Cathelicidin plays a number of roles in the innate immune response. The precursor protein, hCAP18, must be cleaved to its major peptide LL-37 to be active. In addition to its antimicrobial properties, LL-37 can stimulate the release of cytokines such as IL-6 and IL-10 through G protein-coupled receptors, and IL-18 through ERK/P38 pathways, stimulate the EGF receptor leading to activation of STAT1 and 3, induce the chemotaxis of neutrophils, monocytes, macrophages, and T cells into the skin, and promote keratinocyte proliferation and migration (Schauber and Gallo, 2008). The expression of this AMP is induced by 1,25(OH)2D in both myeloid and epithelial cells (Gombart et al., 2005; Wang et al., 2004). In addition, 1,25(OH)2D induces the coreceptor CD14 in keratinocytes (Schauber et al., 2007). Stimulation of TLR2 by an AMP in macrophages (Liu et al., 2006) or stimulation of TLR2 in keratinocytes by wounding the epidermis (Schauber et al., 2007) results in increased expression of CYP27B1, which in the presence of adequate substrate (25OHD) stimulates the expression of cathelicidin. Lack of substrate (25OHD) or lack of CYP27B1 blunts the ability of these cells to respond to a challenge with respect to cathelicidin and/or CD14 production (Liu et al., 2006; Schauber et al., 2007; Wang et al., 2004). In diseases such as atopic dermatitis, the production of cathelicidin and other AMPs is reduced, predisposing these patients to microbial superinfections (Ong et al., 2002). Th2 cytokines such as IL-4 and 13 suppress the induction of AMPs (Howell et al., 2006). Since 1,25(OH)2D stimulates the differentiation of Th2 cells, in this disease 1,25(OH)2D administration may be harmful. An important role of these AMPs besides their antimicrobial properties is to help link the innate and adaptive immune response. Although many cells are capable of the innate immune response, most studies have focused on the macrophage and the keratinocyte. Vitamin D regulation of the innate immune response in these two cell types is comparable, but differences exist.

A. Macrophages The importance of adequate vitamin D nutrition for resistance to certain infections has long been appreciated but poorly understood. This has been especially true for tuberculosis. Indeed, prior to the development of specific drugs for the treatment of tuberculosis, getting out of the city into fresh air and sunlight was the treatment of choice. In a recent survey of patients with tuberculosis in London (Ustianowski et al., 2005), 56% had undetectable

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25OHD levels and an additional 20% had detectable levels but below 9 ng/ ml (22 nM). In 1986, Rook et al. demonstrated that 1,25(OH)2D could inhibit the growth of Mycobacterium tuberculosis. The mechanism for this remained unclear until the publication by Liu et al. (2006) of their results in macrophages. They observed that activation of the toll-like receptor TLR2/1 by a lipoprotein extracted from M. tuberculosis reduced the viability of intracellular M. tuberculosis in human monocytes and macrophages concomitant with increased expression of the VDR and of CYP27B1 in these cells. Killing of M. tuberculosis occurred only when the serum in which the cells were cultured contained adequate levels of 25OHD, the substrate for CYP27B1. This provided clear evidence for the importance of vitamin D nutrition (as manifested by adequate serum levels of 25OHD) in preventing and treating this disease, and demonstrated the critical role for endogenous production of 1,25(OH)2D by the macrophage to enable its antimycobacterial capacity. Activation of TLR2/1 or directly treating these cells with 1,25(OH)2D induced the AMP cathelicidin, which is toxic for M. tuberculosis. If induction of cathelicidin is blocked as with siRNA, the ability of 1,25(OH)2D to enhance the killing of M. tuberculosis is prevented (Liu et al., 2007b). Furthermore, 1,25(OH)2D also induces the production of ROS which if blocked likewise prevents the antimycobacterial activity of 1,25 (OH)2D-treated macrophages (Sly et al., 2001). The murine cathelicidin gene lacks a known VDRE in its promoter, and so might not be expected to be induced by 1,25(OH)2D in mouse cells, yet 1,25(OH)2D stimulates antimycobacterial activity in murine macrophages. Murine macrophages, unlike human macrophages, utilize inducible nitric oxide synthase (iNOS) for their TLR- and 1,25(OH)2D-mediated killing of M. tuberculosis (Brightbill et al., 1999; Sly et al., 2001).

B. Keratinocytes Cathelicidin and CD14 expression in epidermal keratinocytes is also induced by 1,25(OH)2D (Schauber and Gallo, 2008; Schauber et al., 2007, 2008). In these cells, butyrate, which by itself has little effect, potentiates the ability of 1,25(OH)2D to induce cathelicidin (Schauber et al., 2008). Keratinocytes treated with 1,25(OH)2D are substantially more effective in killing Staphylococcus aureus than are untreated keratinocytes. Wounding the epidermis induces the expression of TLR2 and that of its coreceptor CD14 and cathelicidin (Schauber et al., 2007). This does not occur in mice lacking CYP27B1 (Schauber et al., 2007). Unlike macrophages, 1,25(OH)2D stimulates TLR2 expression in keratinocytes as well as in the epidermis when applied topically (Schauber et al., 2007) providing a feed forward loop to amplify the innate immune response. Wounding also increases the expression of CYP27B1, the enzyme that produces 1,25 (OH)2D. This may occur as a result of increased levels of cytokines such

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as TNF-a and IFN-g, both of which we have shown stimulate 1,25(OH)2D production as well as TGF-b and the TLR2 ligand Malp-2 (Schauber et al., 2007). When the levels of VDR or one of its principal coactivators, SRC3, are reduced using siRNA technology, the ability of 1,25(OH)2D to induce cathelicidin and CD14 expression in human keratinocytes is markedly blunted (Schauber et al., 2008).

C. Vitamin D stimulation of the innate immune response may have adverse effects The innate immune system is the first line of defense against invading pathogens. This mechanism initiates the inflammatory response and activates the adaptive arm of the immune defense mechanism (Oppenheim et al., 2007). However, chronic activation of the innate immune response can be deleterious. Cathelicidin has been shown to bind self-DNA forming a complex that is detected by plasmacytoid DCs, perhaps contributing to the psoriatic process (Lande et al., 2007). IL-8/CXCL8, a chemoattractant for polymorphonuclear leukocytes (PMNs), is found in normal gingival tissue. In early stages of periodontitis, IL-8/CXCL8 levels are increased and PMNs are the first cells to respond (Garlet et al., 2005). However, with increasing severity of the infection, IL-8 levels and PMN numbers increase leading to periodontal tissue destruction (Waddington et al., 2000). That said, vitamin D analogs and 1,25(OH)2D itself have proven useful in the treatment of psoriasis, although their role in periodontal disease and other chronic infections has not been established.

VI. Conclusion The immune system defends the body against microbial invasion by activation of both adaptive and innate mechanisms. The innate immune system is the more primitive system prebuilt into cells that are on the front line for defense against bacterial and viral invasion, including epithelial cells in the skin, gut, and lung as well as macrophages and neutrophils. The adaptive immune system provides a more specific response, but takes longer to develop, although once developed provides a powerful response against invading organisms. Vitamin D, via its active metabolite 1,25(OH)2D, regulates both types of immunity, suppressing adaptive immunity but potentiating the innate immune response. Suppression of the adaptive immune response is likely to be useful in combating a variety of autoimmune diseases, and protecting transplanted organs from rejection. Stimulation of the innate immune response at those surfaces exposed to the environment provides a first line of defense against pathogens in the

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environment, and so would be expected to enhance the resistance to acute infections in the skin, lungs, gastrointestinal tract, bladder, and other epithelial surfaces. However, vitamin D signaling may have its down side. As 1,25(OH)2D shifts the repertoire of T cells from Th1/Th17 to Th2, the potential for aggravating atopic diseases such as asthma and atopic dermatitis needs to be considered. Resistance to infections by organisms such as leishmaniasis in which an intact adaptive immune response is crucial for their prevention/treatment may be compromised by vitamin D. In chronic inflammatory states, persistent activation of the innate immune system may perpetuate the inflammatory condition as in psoriasis and periodontal disease. However, the bulk of the evidence supports the concept that vitamin D regulation of the immune system is beneficial, and provides an important rationale to maintain vitamin D sufficiency on a year round basis.

ACKNOWLEDGMENTS This work was supported by Grants RO1 AR050023 and AR051930 from the National Institutes of Health, a Merit Review from the Department of Veterans Affairs, and Grant 07A140 from the American Institute of Cancer Research.

REFERENCES Adamopoulos, I. E., and Bowman, E. P. (2008). Immune regulation of bone loss by Th17 cells. Arthritis Res. Ther. 10, 225. Adorini, L. (2005). Intervention in autoimmunity: The potential of vitamin D receptor agonists. Cell. Immunol. 233, 115–124. Adorini, L., and Penna, G. (2008). Control of autoimmune diseases by the vitamin D endocrine system. Nat. Clin. Pract. Rheumatol. 4, 404–412. Andersson, S., Davis, D. L., Dahlba¨ck, H., Jo¨rnvall, H., and Russell, D. W. (1989). Cloning, structure, and expression of the mitochondrial cytochrome P-450 sterol 26-hydroxylase, a bile acid biosynthetic enzyme. J. Biol. Chem. 264, 8222–8229. Armbrecht, H. J., Forte, L. R., Wongsurawat, N., Zenser, T. V., and Davis, B. B. (1984). Forskolin increases 1,25-dihydroxyvitamin D3 production by rat renal slices in vitro. Endocrinology 114, 644–649. Ascherio, A., Munger, K. L., and Simon, K. C. (2010). Vitamin D and multiple sclerosis. Lancet Neurol. 9, 599–612. Back, O., Blomquist, H. K., Hernell, O., and Stenberg, B. (2009). Does vitamin D intake during infancy promote the development of atopic allergy? Acta Derm. Venereol. 89, 28–32. Baroni, E., Biffi, M., Benigni, F., Monno, A., Carlucci, D., Carmeliet, G., Bouillon, R., and D’Ambrosio, D. (2007). VDR-dependent regulation of mast cell maturation mediated by 1,25-dihydroxyvitamin D3. J. Leukoc. Biol. 81, 250–262. Berginer, V. M., Shany, S., Alkalay, D., Berginer, J., Dekel, S., Salen, G., Tint, G. S., and Gazit, D. (1993). Osteoporosis and increased bone fractures in cerebrotendinous xanthomatosis. Metabolism 42, 69–74. Bikle, D. D. (2009). Nonclassical actions of vitamin D. J. Endocrinol. Metab. 94, 26–34.

Vitamin D and Immune Function

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Bikle, D. (2010). Extra renal synthesis of 1,25-dihydroxyvitamin D and its health implications. In “Vitamin D: Physiology, Molecular Biology, and Clinical Applications,” (M. Holick, Ed.), pp. 277–295. Humana Press, New York. Bikle, D. D., and Pillai, S. (1993). Vitamin D, calcium, and epidermal differentiation. Endocr. Rev. 14, 3–19. Bikle, D. D., Pillai, S., Gee, E., and Hincenbergs, M. (1989). Regulation of 1,25-dihydroxyvitamin D production in human keratinocytes by interferon-gamma. Endocrinology 124, 655–660. Bikle, D. D., Pillai, S., Gee, E., and Hincenbergs, M. (1991). Tumor necrosis factor-alpha regulation of 1,25-dihydroxyvitamin D production by human keratinocytes. Endocrinology 129, 33–38. Bitetto, D., Fabris, C., Falleti, E., Fornasiere, E., Fumolo, E., Fontanini, E., Cussigh, A., Occhino, G., Baccarani, U., Pirisi, M., and Toniutto, P. (2010). Vitamin D and the risk of acute allograft rejection following human liver transplantation. Liver Int. 30, 417–444. Bouillon, R., Carmeliet, G., Verlinden, L., van Etten, E., Verstuyf, A., Luderer, H. F., Lieben, L., Mathieu, C., and Demay, M. (2008). Vitamin D and human health: Lessons from vitamin D receptor null mice. Endocr. Rev. 29, 726–776. Brehm, J. M., Schuemann, B., Fuhlbrigge, A. L., Hollis, B. W., Strunk, R. C., Zeiger, R. S., Weiss, S. T., and Litonjua, A. A. (2010). Serum vitamin D levels and severe asthma exacerbations in the Childhood Asthma Management Program study. J. Allergy Clin. Immunol. 126, 52–58. Brenza, H. L., Kimmel-Jehan, C., Jehan, F., Shinki, T., Wakino, S., Anazawa, H., Suda, T., and DeLuca, H. F. (1998). Parathyroid hormone activation of the 25-hydroxyvitamin D3-1alpha-hydroxylase gene promoter. Proc. Natl. Acad. Sci. USA 95, 1387–1391. Brightbill, H. D., Libraty, D. H., Krutzik, S. R., Yang, R. B., Belisle, J. T., Bleharski, J. R., Maitland, M., Norgard, M. V., Plevy, S. E., Smale, S. T., Brennan, P. J., Bloom, B. R., et al. (1999). Host defense mechanisms triggered by microbial lipoproteins through tolllike receptors. Science 285, 732–736. Cali, J. J., and Russell, D. W. (1991). Characterization of human sterol 27-hydroxylase. A mitochondrial cytochrome P-450 that catalyzes multiple oxidation reaction in bile acid biosynthesis. J. Biol. Chem. 266, 7774–7778. Cali, J. J., Hsieh, C. L., Francke, U., and Russell, D. W. (1991). Mutations in the bile acid biosynthetic enzyme sterol 27-hydroxylase underlie cerebrotendinous xanthomatosis. J. Biol. Chem. 266, 7779–7783. Chen, S., Sims, G. P., Chen, X. X., Gu, Y. Y., Chen, S., and Lipsky, P. E. (2007). Modulatory effects of 1,25-dihydroxyvitamin D3 on human B cell differentiation. J. Immunol. 179, 1634–1647. Cheng, J. B., Motola, D. L., Mangelsdorf, D. J., and Russell, D. W. (2003). De-orphanization of cytochrome P450 2R1: A microsomal vitamin D 25-hydroxilase. J. Biol. Chem. 278, 38084–38093. Cheng, J. B., Levine, M. A., Bell, N. H., Mangelsdorf, D. J., and Russell, D. W. (2004). Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase. Proc. Natl. Acad. Sci. USA 101, 7711–7715. Daniel, C., Sartory, N. A., Zahn, N., Radeke, H. H., and Stein, J. M. (2008). Immune modulatory treatment of trinitrobenzene sulfonic acid colitis with calcitriol is associated with a change of a T helper (Th) 1/Th17 to a Th2 and regulatory T cell profile. J. Pharmacol. Exp. Ther. 324, 23–33. Dardenne, O., Prud’homme, J., Arabian, A., Glorieux, F. H., and St-Arnaud, R. (2001). Targeted inactivation of the 25-hydroxyvitamin D(3)-1(alpha)-hydroxylase gene (CYP27B1) creates an animal model of pseudovitamin D-deficiency rickets. Endocrinology 142, 3135–3141.

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Ehrchen, J., Helming, L., Varga, G., Pasche, B., Loser, K., Gunzer, M., Sunderkotter, C., Sorg, C., Roth, J., and Lengeling, A. (2007). Vitamin D receptor signaling contributes to susceptibility to infection with Leishmania major. FASEB J. 21, 3208–3218. Froicu, M., Weaver, V., Wynn, T. A., McDowell, M. A., Welsh, J. E., and Cantorna, M. T. (2003). A crucial role for the vitamin D receptor in experimental inflammatory bowel diseases. Mol. Endocrinol. 17, 2386–2392. Fu, G. K., Lin, D., Zhang, M. Y., Bikle, D. D., Shackleton, C. H., Miller, W. L., and Portale, A. A. (1997). Cloning of human 25-hydroxyvitamin D-1 alpha-hydroxylase and mutations causing vitamin D-dependent rickets type 1. Mol. Endocrinol. 11, 1961–1970. Garlet, G. P., Avila-Campos, M. J., Milanezi, C. M., Ferreira, B. R., and Silva, J. S. (2005). Actinobacillus actinomycetemcomitans-induced periodontal disease in mice: Patterns of cytokine, chemokine, and chemokine receptor expression and leukocyte migration. Microbes Infect. 7, 738–747. Gombart, A. F., Borregaard, N., and Koeffler, H. P. (2005). Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly upregulated in myeloid cells by 1,25-dihydroxyvitamin D3. FASEB J. 19, 1067–1077. Gregori, S., Casorati, M., Amuchastegui, S., Smiroldo, S., Davalli, A. M., and Adorini, L. (2001). Regulatory T cells induced by 1 alpha,25-dihydroxyvitamin D3 and mycophenolate mofetil treatment mediate transplantation tolerance. J. Immunol. 167, 1945–1953. Gyetko, M. R., Hsu, C. H., Wilkinson, C. C., Patel, S., and Young, E. (1993). Monocyte 1 alpha-hydroxylase regulation: Induction by inflammatory cytokines and suppression by dexamethasone and uremia toxin. J. Leukoc. Biol. 54, 17–22. Gysemans, C., van Etten, E., Overbergh, L., Giulietti, A., Eelen, G., Waer, M., Verstuyf, A., Bouillon, R., and Mathieu, C. (2008). Unaltered diabetes presentation in NOD mice lacking the vitamin D receptor. Diabetes 57, 269–275. Hansdottir, S., Monick, M. M., Hinde, S. L., Lovan, N., Look, D. C., and Hunninghake, G. W. (2008). Respiratory epithelial cells convert inactive vitamin D to its active form: Potential effects on host defense. J. Immunol. 181, 7090–7099. Henry, H. L. (1985). Parathyroid hormone modulation of 25-hydroxyvitamin D3 metabolism by cultured chick kidney cells is mimicked and enhanced by forskolin. Endocrinology 116, 503–510. Horiuchi, N., Suda, T., Takahashi, H., Shimazawa, E., and Ogata, E. (1977). In vivo evidence for the intermediary role of 30 ,50 -cyclic AMP in parathyroid hormone-induced stimulation of 1alpha,25-dihydroxyvitamin D3 synthesis in rats. Endocrinology 101, 969–974. Howell, M. D., Gallo, R. L., Boguniewicz, M., Jones, J. F., Wong, C., Streib, J. E., and Leung, D. Y. (2006). Cytokine milieu of atopic dermatitis skin subverts the innate immune response to vaccinia virus. Immunity 24, 341–348. Ichikawa, F., Sato, K., Nanjo, M., Nishii, Y., Shinki, T., Takahashi, N., and Suda, T. (1995). Mouse primary osteoblasts express vitamin D3 25-hydroxylase mRNA and convert 1 alpha-hydroxyvitamin D3 into 1 alpha,25-dihydroxyvitamin D3. Bone 16, 129–135. Janulis, M., Tembe, V., and Favus, M. J. (1992). Role of protein kinase C in parathyroid hormone stimulation of renal 1,25-dihydroxyvitamin D3 secretion. J. Clin. Invest. 90, 2278–2283. Janulis, M., Wong, M. S., and Favus, M. J. (1993). Structure-function requirements of parathyroid hormone for stimulation of 1,25-dihydroxyvitamin D3 production by rat renal proximal tubules. Endocrinology 133, 713–719. Josien, R., Li, H. L., Ingulli, E., Sarma, S., Wong, B. R., Vologodskaia, M., Steinman, R. M., and Choi, Y. (2000). TRANCE, a tumor necrosis factor family member, enhances the longevity and adjuvant properties of dendritic cells in vivo. J. Exp. Med. 191, 495–502.

Vitamin D and Immune Function

19

Kato, S., Fujiki, R., Kim, M. S., and Kitagawa, H. (2007). Ligand-induced transrepressive function of VDR requires a chromatin remodeling complex, WINAC. J. Steroid Biochem. Mol. Biol. 103, 372–380. Kitanaka, S., Takeyama, K., Murayama, A., Sato, T., Okumura, K., Nogami, M., Hasegawa, Y., Niimi, H., Yanagisawa, J., Tanaka, T., and Kato, S. (1998). Inactivating mutations in the 25-hydroxyvitamin D3 1alpha-hydroxylase gene in patients with pseudovitamin D-deficiency rickets. N. Engl. J. Med. 338, 653–661. Knip, M., Virtanen, S. M., and Akerblom, H. K. (2010). Infant feeding and the risk of type 1 diabetes. Am. J. Clin. Nutr. 91, 1506S–1513S. Lande, R., Gregorio, J., Facchinetti, V., Chatterjee, B., Wang, Y. H., Homey, B., Cao, W., Wang, Y. H., Su, B., Nestle, F. O., Zal, T., Mellman, I., et al. (2007). Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature 449, 564–569. Lehmann, B., Querings, K., and Reichrath, J. (2004). Vitamin D and skin: New aspects for dermatology. Exp. Dermatol. 13(Suppl. 4), 11–15. Leitersdorf, E., Reshef, A., Meiner, V., Levitzki, R., Schwartz, S. P., Dann, E. J., Berkman, N., Cali, J. J., Klapholz, L., and Berginer, V. M. (1993). Frameshift and splice-junction mutations in the sterol 27-hydroxylase gene cause cerebrotendinous xanthomatosis in Jews or Moroccan origin. J. Clin. Invest. 91, 2488–2496. Leitersdorf, E., Safadi, R., Meiner, V., Reshef, A., Bjo¨rkhem, I., Friedlander, Y., Morkos, S., and Berginer, V. M. (1994). Cerebrotendinous xanthomatosis in the Israeli Druze: Molecular genetics and phenotypic characteristics. Am. J. Hum. Genet. 55, 907–915. Liu, P. T., Stenger, S., Li, H., Wenzel, L., Tan, B. H., Krutzik, S. R., Ochoa, M. T., Schauber, J., Wu, K., Meinken, C., Kamen, D. L., Wagner, M., et al. (2006). Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 311, 1770–1773. Liu, P. T., Krutzik, S. R., and Modlin, R. L. (2007a). Therapeutic implications of the TLR and VDR partnership. Trends Mol. Med. 13, 117–124. Liu, P. T., Stenger, S., Tang, D. H., and Modlin, R. L. (2007b). Cutting edge: Vitamin Dmediated human antimicrobial activity against Mycobacterium tuberculosis is dependent on the induction of cathelicidin. J. Immunol. 179, 2060–2063. Loser, K., Mehling, A., Loeser, S., Apelt, J., Kuhn, A., Grabbe, S., Schwarz, T., Penninger, J. M., and Beissert, S. (2006). Epidermal RANKL controls regulatory Tcell numbers via activation of dendritic cells. Nat. Med. 12, 1372–1379. Mathieu, C., Van Etten, E., Gysemans, C., Decallonne, B., Kato, S., Laureys, J., Depovere, J., Valckx, D., Verstuyf, A., and Bouillon, R. (2001). In vitro and in vivo analysis of the immune system of vitamin D receptor knockout mice. J. Bone Miner. Res. 16, 2057–2065. O’Kelly, J., Hisatake, J., Hisatake, Y., Bishop, J., Norman, A., and Koeffler, H. P. (2002). Normal myelopoiesis but abnormal T lymphocyte responses in vitamin D receptor knockout mice. J. Clin. Invest. 109, 1091–1099. Ong, P. Y., Ohtake, T., Brandt, C., Strickland, I., Boguniewicz, M., Ganz, T., Gallo, R. L., and Leung, D. Y. (2002). Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N. Engl. J. Med. 347, 1151–1160. Oppenheim, J. J., Tewary, P., de la Rosa, G., and Yang, D. (2007). Alarmins initiate host defense. Adv. Exp. Med. Biol. 601, 185–194. Pryke, A. M., Duggan, C., White, C. P., Posen, S., and Mason, R. S. (1990). Tumor necrosis factor-alpha induces vitamin D-1-hydroxylase activity in normal human alveolar macrophages. J. Cell. Physiol. 142, 652–656. Rajapakse, R., Mousli, M., Pfaff, A. W., Uring-Lambert, B., Marcellin, L., Bronner, C., Jeanblanc, M., Villard, O., Letscher-Bru, V., Klein, J. P., and Candolfi, E. (2005).

20

Daniel D. Bikle

1, 25-Dihydroxyvitamin D3 induces splenocyte apoptosis and enhances BALB/c mice sensitivity to toxoplasmosis. J. Steroid Biochem. Mol. Biol. 96, 179–185. Rasmussen, H., Wong, M., Bikle, D., and Goodman, D. B. (1972). Hormonal control of the renal conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol. J. Clin. Invest. 51, 2502–2504. Ren, S., Nguyen, L., Wu, S., Encinas, C., Adams, J. S., and Hewison, M. (2005). Alternative splicing of vitamin D-24-hydroxylase: A novel mechanism for the regulation of extrarenal 1,25-dihydroxyvitamin D synthesis. J. Biol. Chem. 280, 20604–20611. Rook, G. A., Steele, J., Fraher, L., Barker, S., Karmali, R., O’Riordan, J., and Stanford, J. (1986). Vitamin D3, gamma interferon, and control of proliferation of Mycobacterium tuberculosis by human monocytes. Immunology 57, 159–163. Rost, C. R., Bikle, D. D., and Kaplan, R. A. (1981). In vitro stimulation of 25-hydroxycholecalciferol 1alpha-hydroxylation by parathyroid hormone in chick kidney slices: Evidence for a role for adenosine 30 ,50 -monophosphate. Endocrinology 108, 1002–1006. Saito, H., Kusano, K., Kinosaki, M., Ito, H., Hirata, M., Segawa, H., Miyamoto, K., and Fukushima, N. (2003). Human fibroblast growth factor-23 mutants suppress Naþdependent phosphate co-transport activity and 1alpha,25-dihydroxyvitamin D3 production. J. Biol. Chem. 278, 2206–2211. Sakaguchi, S., Yamaguchi, T., Nomura, T., and Ono, M. (2008). Regulatory T cells and immune tolerance. Cell 133, 775–787. Schauber, J., and Gallo, R. L. (2008). The vitamin D pathway: A new target for control of the skin’s immune response? Exp. Dermatol. 17, 633–639. Schauber, J., Dorschner, R. A., Coda, A. B., Buchau, A. S., Liu, P. T., Kiken, D., Helfrich, Y. R., Kang, S., Elalieh, H. Z., Steinmeyer, A., Zugel, U., Bikle, D. D., et al. (2007). Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D-dependent mechanism. J. Clin. Invest. 117, 803–811. Schauber, J., Oda, Y., Buchau, A. S., Yun, Q. C., Steinmeyer, A., Zugel, U., Bikle, D. D., and Gallo, R. L. (2008). Histone acetylation in keratinocytes enables control of the expression of cathelicidin and CD14 by 1,25-dihydroxyvitamin D(3). J. Invest. Dermatol. 128, 816–824. Schuster, I., Egger, H., Astecker, N., Herzig, G., Schussler, M., and Vorisek, G. (2001). Selective inhibitors of CYP24: Mechanistic tools to explore vitamin D metabolism in human keratinocytes. Steroids 66, 451–462. Shimada, T., Mizutani, S., Muto, T., Yoneya, T., Hino, R., Takeda, S., Takeuchi, Y., Fujita, T., Fukumoto, S., and Yamashita, T. (2001). Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc. Natl. Acad. Sci. USA 98, 6500–6505. Sigmundsdottir, H., Pan, J., Debes, G. F., Alt, C., Habtezion, A., Soler, D., and Butcher, E. C. (2007). DCs metabolize sunlight-induced vitamin D3 to ‘program’ T cell attraction to the epidermal chemokine CCL27. Nat. Immunol. 8, 285–293. Sly, L. M., Lopez, M., Nauseef, W. M., and Reiner, N. E. (2001). 1alpha,25-Dihydroxyvitamin D3-induced monocyte antimycobacterial activity is regulated by phosphatidylinositol 3-kinase and mediated by the NADPH-dependent phagocyte oxidase. J. Biol. Chem. 276, 35482–35493. Soumelis, V., Reche, P. A., Kanzler, H., Yuan, W., Edward, G., Homey, B., Gilliet, M., Ho, S., Antonenko, S., Lauerma, A., Smith, K., Gorman, D., et al. (2002). Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat. Immunol. 3, 673–680. St-Arnaud, R., Messerlian, S., Moir, J. M., Omdahl, J. L., and Glorieux, F. H. (1997). The 25-hydroxyvitamin D 1-alpha-hydroxylase gene maps to the pseudovitamin D-deficiency rickets (PDDR) disease locus. J. Bone Miner. Res. 12, 1552–1559.

Vitamin D and Immune Function

21

Stoffels, K., Overbergh, L., Giulietti, A., Verlinden, L., Bouillon, R., and Mathieu, C. (2006). Immune regulation of 25-hydroxyvitamin-D3-1alpha-hydroxylase in human monocytes. J. Bone Miner. Res. 21, 37–47. Topilski, I., Flaishon, L., Naveh, Y., Harmelin, A., Levo, Y., and Shachar, I. (2004). The anti-inflammatory effects of 1,25-dihydroxyvitamin D3 on Th2 cells in vivo are due in part to the control of integrin-mediated T lymphocyte homing. Eur. J. Immunol. 34, 1068–1076. Ustianowski, A., Shaffer, R., Collin, S., Wilkinson, R. J., and Davidson, R. N. (2005). Prevalence and associations of vitamin D deficiency in foreign-born persons with tuberculosis in London. J. Infect. 50, 432–437. Usui, E., Noshiro, M., and Okuda, K. (1990). Molecular cloning of cDNA for vitamin D3 25-hydroxylase from rat liver mitochondria. FEBS Lett. 262, 135–138. van Etten, E., and Mathieu, C. (2005). Immunoregulation by 1,25-dihydroxyvitamin D3: Basic concepts. J. Steroid Biochem. Mol. Biol. 97, 93–101. Vidal, M., Ramana, C. V., and Dusso, A. S. (2002). Stat1-vitamin D receptor interactions antagonize 1,25-dihydroxyvitamin D transcriptional activity and enhance stat1-mediated transcription. Mol. Cell. Biol. 22, 2777–2787. Waddington, R. J., Moseley, R., and Embery, G. (2000). Reactive oxygen species: A potential role in the pathogenesis of periodontal diseases. Oral Dis. 6, 138–151. Wang, J. T., Lin, C. J., Burridge, S. M., Fu, G. K., Labuda, M., Portale, A. A., and Miller, W. L. (1998). Genetics of vitamin D 1alpha-hydroxylase deficiency in 17 families. Am. J. Hum. Genet. 63, 1694–1702. Wang, T. T., Nestel, F. P., Bourdeau, V., Nagai, Y., Wang, Q., Liao, J., TaveraMendoza, L., Lin, R., Hanrahan, J. W., Mader, S., and White, J. H. (2004). Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J. Immunol. 173, 2909–2912. White, K. E., Evans, W. E., O’Riordan, J. L. H., Speer, M. C., Econs, M. J., LorenzDepiereux, B., Grabowski, M., Meitinger, T., and Strom, T. M. (2000). Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat. Genet. 26, 345. Wittke, A., Weaver, V., Mahon, B. D., August, A., and Cantorna, M. T. (2004). Vitamin D receptor-deficient mice fail to develop experimental allergic asthma. J. Immunol. 173, 3432–3436. Wittke, A., Chang, A., Froicu, M., Harandi, O. F., Weaver, V., August, A., Paulson, R. F., and Cantorna, M. T. (2007). Vitamin D receptor expression by the lung micro-environment is required for maximal induction of lung inflammation. Arch. Biochem. Biophys. 460, 306–313. Xie, Z., Munson, S., Huang, N., Schuster, I., Portale, A. A., Miller, W. L., and Bikle, D. D. (2001). The mechanism of 1,25-dihydroxyvitamin D3 auto-regulation in keratinocytes. J. Bone Miner. Res. 16(Suppl. 1), S556. Zasloff, M. (2005). Sunlight, vitamin D, and the innate immune defenses of the human skin. J. Invest. Dermatol. 125, xvi–xvii.

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Vitamin D and Innate and Adaptive Immunity Martin Hewison

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I. Introduction II. Antibacterial Actions of Vitamin D A. Vitamin D bioavailability and antibacterial activity B. Innate immune responses and the regulation of vitamin D metabolism C. VDR expression and innate immune responses D. Antibacterial targets for vitamin D E. Antibacterial effects of vitamin D in neutrophils and other cell types III. Vitamin D and Antigen Presentation A. Vitamin D and DC maturation B. Vitamin D metabolism and DC function IV. Vitamin D and Adaptive Immunity A. Vitamin D, T-cell activation and proliferation B. Vitamin D, T-helper cells and cytotoxic T-cells C. Vitamin D and regulatory T-cells D. Vitamin D and B-cell function V. Vitamin D, the Immune System and Human Health A. Vitamin D and tuberculosis B. Vitamin D and type 1 diabetes C. Vitamin D and MS D. Vitamin D and inflammatory bowel disease VI. Conclusions and Future Directions References

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Abstract In the last 5 years there has been renewed interest in the health benefits of vitamin D. A central feature of this revival has been new information concerning the nonclassical effects of vitamin D. In particular, studies of the interaction Department of Orthopaedic Surgery and Molecular Biology Institute, David Geffen School of Medicine at UCLA, Los Angeles, California, USA Vitamins and Hormones, Volume 86 ISSN 0083-6729, DOI: 10.1016/B978-0-12-386960-9.00002-2

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2011 Elsevier Inc. All rights reserved.

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Martin Hewison

between vitamin D and the immune system have highlighted the importance of localized conversion of precursor 25-hydroxyvitamin D (25OHD) to active 1,25dihydroxyvitamin D (1,25(OH)2D) as a mechanism for maintaining antibacterial activity in humans. The clinical relevance of this has been endorsed by increasing evidence of suboptimal 25OHD status in populations across the globe. Collectively these observations support the hypothesis that vitamin D insufficiency may lead to dysregulation of human immune responses and may therefore be an underlying cause of infectious disease and immune disorders. The current review describes the key mechanisms associated with vitamin D metabolism and signaling for both innate immune (antimicrobial activity and antigen presentation) and adaptive immune (T and B lymphocyte function) responses. These include coordinated actions of the vitamin D-activating enzyme, 1a-hydroxylase (CYP27B1), and the vitamin D receptor (VDR) in mediating intracrine and paracrine actions of vitamin D. Finally, the review will consider the role of immunomodulatory vitamin D in human health, with specific emphasis on infectious and autoimmune disease. ß 2011 Elsevier Inc.

I. Introduction In the last 5 years vitamin D has undergone a renaissance. A simple search of Pubmed from 2000 to 2005 identifies approximately 8000 entries for the term “vitamin D.” This is almost identical to the number of entries for “thyroid hormone” over the same period. A similar search for “vitamin D” over the years 2005–2010 shows 11,200 entries, a 40% increase on the previous 5 years. This contrasts with 9000 entries for “thyroid hormone,” a 12% increase over the previous 5 years. Two key factors have contributed to this. The first concerns our current view of what constitutes adequate vitamin D status. Until recently, the vitamin D status of an individual was defined simply by presence or absence of the bone disease rickets (osteomalacia in adults). Rachitic bone disease associated with vitamin D deficiency is relatively rare but it is now clear that suboptimal vitamin D status can occur in the absence of rachitic bone disease. This new perspective on vitamin D status arose from the observation that serum levels of the main circulating form of vitamin D (25OHD) as high as 75 nM correlate inversely with serum parathyroid hormone (PTH) concentrations (Chapuy et al., 1997). As a result, new terminology for suboptimal vitamin D status has been introduced. Vitamin D “insufficiency” now refers to serum levels of 25OHD that are suboptimal (