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IL-15 Links TLR2/1-Induced Macrophage Differentiation to the Vitamin D-Dependent Antimicrobial Pathway

Stephan R. Krutzik^*, Martin Hewison, Philip T. Liu^*, Juan Antonio Robles^*, Steffen Stenger, John S. Adams and Robert L. Modlin^1,*,

^* Division of Dermatology, University of California Los Angeles/Orthopaedic Hospital Department of Orthopedic Surgery and Department of Microbiology and Immunology, David Geffen School of Medicine at University of California Los Angeles, CA 90095; and Boyer Hall, Institute for Clinical Microbiology and Hygiene, University Hospital, Ulm, Germany

An essential function of the innate immune system is to directly trigger antimicrobial mechanisms to defend against invading pathogens. In humans, one such pathway involves activation by TLR2/1L leading to the vitamin D-dependent induction of antimicrobial peptides. In this study, we found that TLR2/1-induced IL-15 was required for induction of CYP27b1, the VDR and the downstream antimicrobial peptide cathelicidin. Although both IL-15 and IL-4 triggered macrophage differentiation, only IL-15 was sufficient by itself to induce CYP27b1 and subsequent bioconversion of 25-hydroxyvitamin D3 (25D3) into bioactive 1,25D3, leading to VDR activation and induction of cathelicidin. Finally, IL-15-differentiated macrophages could be triggered by 25D3 to induce an antimicrobial activity against intracellular Mycobacterium tuberculosis. Therefore, IL-15 links TLR2/1-induced macrophage differentiation to the vitamin D-dependent antimicrobial pathway.

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 Address correspondence and reprint requests to Dr. Robert L. Modlin, University of California Los Angeles, Division of Dermatology, 52–121 CHS, 10833 Le Conte Avenue, Los Angeles, CA 90095. E-mail address: rmodlin{at}mednet.ucla.edu

² Abbreviations used in this paper: iDC, immature dendritic cell; M, macrophage; VDR, vitamin D receptor.

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

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