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Respiratory Epithelial Cells Convert Inactive Vitamin D to Its Active Form: Potential Effects on Host Defense¹

Department of Medicine, University of Iowa Carver College of Medicine, and Veterans Administration Medical Center, Iowa City, IA 52242

The role of vitamin D in innate immunity is increasingly recognized. Recent work has identified a number of tissues that express the enzyme 1-hydroxylase and are able to activate vitamin D. This locally produced vitamin D is believed to have important immunomodulatory effects. In this paper, we show that primary lung epithelial cells express high baseline levels of activating 1-hydroxylase and low levels of inactivating 24-hydroxylase. The result of this enzyme expression is that airway epithelial cells constitutively convert inactive 25-dihydroxyvitamin D₃ to the active 1,25-dihydroxyvitamin D₃. Active vitamin D that is generated by lung epithelium leads to increased expression of vitamin D-regulated genes with important innate immune functions. These include the cathelicidin antimicrobial peptide gene and the TLR coreceptor CD14. dsRNA increases the expression of 1-hydroxylase, augments the production of active vitamin D, and synergizes with vitamin D to increase expression of cathelicidin. In contrast to induction of the antimicrobial peptide, vitamin D attenuates dsRNA-induced expression of the NF-B-driven gene IL-8. We conclude that primary epithelial cells generate active vitamin D, which then influences the expression of vitamin D-driven genes that play a major role in host defense. Furthermore, the presence of vitamin D alters induction of antimicrobial peptides and inflammatory cytokines in response to viruses. These observations suggest a novel mechanism by which local conversion of inactive to active vitamin D alters immune function in the lung.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a Veterans Administration Merit Review grant and by National Institutes of Health Grants HL-60316, HL-077431, and HL-079901-01A1 (to G.W.H.) and by Grant RR00059 from the General Clinical Research Centers Program, National Center for Research Resources, National Institutes of Health.

² Address correspondence and reprint requests to Dr. Sif Hansdottir, University of Iowa Hospitals and Clinics, Division of Pulmonary, Critical Care, 200 Hawkins Drive, C323GH, Iowa City, IA 52242-1081. E-mail address: sif-hansdottir{at}uiowa.edu

³ Abbreviations used in this paper: 25D₃, 25-hydroxyvitamin D₃; 1,25D₃, 1,25-dihydroxyvitamin D₃; VDR, vitamin D receptor; VDRE, vitamin D-responsive element; SRC, steroid receptor coactivator; poly(IC), polyinosinic-polycytidylic acid; hTBE, human tracheobronchial epithelial; RSV, respiratory syncytial virus; PVDF, polyvinylidene difluoride; HAT, histone acetyltransferase; CPB, CREB-binding protein; HDAC, histone deacetylase; RIG-I, retinoic acid-inducible gene I; MDA-5, melanoma differentiation-associated gene 5; PTH, parathyroid hormone.

⁴ The online version of this article contains supplemental material.

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The JI 2008 181: 6677-6678. [Full Text]