T-cell cytokines differentially control human monocyte antimicrobial responses by regulating vitamin D metabolism.

Edfeldt, Kristina; Liu, Philip T; Chun, Rene; Fabri, Mario; Schenk, Mirjam; Wheelwright, Matthew; Keegan, Caroline; Krutzik, Stephan R; Adams, John S; Hewison, Martin; Modlin, Robert L (2010). T-cell cytokines differentially control human monocyte antimicrobial responses by regulating vitamin D metabolism. Proceedings of the National Academy of Sciences of the United States of America - PNAS, 107(52), pp. 22593-22598. National Academy of Sciences NAS 10.1073/pnas.1011624108

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We investigated the mechanisms by which T-cell cytokines are able to influence the Toll-like receptor (TLR)-induced, vitamin D-dependent antimicrobial pathway in human monocytes. T-cell cytokines differentially influenced TLR2/1-induced expression of the antimicrobial peptides cathelicidin and DEFB4, being up-regulated by IFN-γ, down-regulated by IL-4, and unaffected by IL-17. The Th1 cytokine IFN-γ up-regulated TLR2/1 induction of 25-hydroxyvitamin D-1α-hydroxylase (i.e., CYP27B1), leading to enhanced bioconversion of 25-hydroxyvitamin D(3) (25D(3)) to its active metabolite 1,25D(3). In contrast, the Th2 cytokine IL-4, by itself and in combination with the TLR2/1 ligand, induced catabolism of 25D(3) to the inactive metabolite 24,25D(3), and was dependent on expression of vitamin D-24-hydroxylase (i.e., CYP24A1). Therefore, the ability of T-cell cytokines to differentially control monocyte vitamin D metabolism represents a mechanism by which cell-mediated immune responses can regulate innate immune mechanisms to defend against microbial pathogens.

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