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* University of California at Los Angeles/Orthopaedic Hospital Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA 90095;
Molecular Biology Institute, University of California at Los Angeles, Los Angeles, CA 90095;
Division of Endocrinology, Diabetes and Metabolism, Burns and Allen Research Center, Cedars-Sinai Medical Center, David Geffen School of Medicine, 8700 Beverly Boulevard, Los Angeles, CA 90048;
Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles 90095;
¶ Linus Pauling Institute, Oregon State University, Corvallis, OE 97331; and
|| The Granulocyte Research Laboratory, Department of Hematology, Rigshospitalet 9322, 9 Blegdamsvej, Copenhagen, Denmark
The active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)2D) enhances innate immunity by inducing the cathelicidin antimicrobial peptide (hCAP). In monocytes/macrophages, this occurs primarily in response to activation of TLR, that induce expression of the vitamin D receptor and localized synthesis of 1,25(OH)2D from precursor 25-hydroxyvitamin D3 (25OHD). To clarify the relationship between vitamin D and innate immunity, we assessed changes in hCAP expression in vivo and ex vivo in human subjects attending a bone clinic (n = 50). Of these, 38% were vitamin D-insufficient (<75 nM 25OHD) and received supplementation with vitamin D (50,000 IU vitamin D2 twice weekly for 5 wk). Baseline 25OHD status or vitamin D supplementation had no effect on circulating levels of hCAP. Therefore, ex vivo changes in hCAP for each subject were assessed using peripheral blood monocytes cultured with 10% autologous serum (n = 28). Under these vitamin D "insufficient" conditions the TLR2/1 ligand 19 kDa lipopeptide or the TLR4 ligand LPS, monocytes showed increased expression of the vitamin D-activating enzyme CYP27b1 (5- and 5.5-fold, respectively, both p < 0.01) but decreased expression of hCAP mRNA (10-fold and 30-fold, both p < 0.001). Following treatment with 19 kDa, expression of hCAP: 1) correlated with 25OHD levels in serum culture supplements (R = 0.649, p < 0.001); 2) was significantly enhanced by exogenous 25OHD (5 nM); and 3) was significantly enhanced with serum from vivo vitamin D-supplemented patients. These data suggest that a key role of vitamin D in innate immunity is to maintain localized production of antibacterial hCAP following TLR activation of monocytes.
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 National Institutes of Health Grant RO1AR050626 (to M.H.) and a Winnick Family Clinical Scholarship (to M.H.). P.T.L. is supported by the Microbial Pathogenesis Training Grant 2-T32-AI-07323.
2 Address correspondence and reprint requests to Dr. Martin Hewison, Department of Orthopaedic Surgery, David Geffen School of Medicine, University of California at Los Angeles, 615 Charles E. Young Drive South, Los Angeles, CA 90095. E-mail address: mhewison{at}mednet.ucla.edu
3 Abbreviations used in this paper: VDR, vitamin D receptor; 25OHD, 25-hydroxyvitamin D; hCAP, cathelicidin antimicrobial protein; M. tb, Mycobacterium tuberculosis.
4 The online version of this article contains supplementary material.
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