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

Research output: Contribution to journalArticle

Authors

  • Kristina Edfeldt
  • Philip T Liu
  • Rene Chun
  • Mario Fabri
  • Mirjam Schenk
  • Matthew Wheelwright
  • Caroline Keegan
  • Stephan R Krutzik
  • John S Adams
  • Robert L Modlin

Colleges, School and Institutes

Abstract

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.

Details

Original languageEnglish
Pages (from-to)22593-8
Number of pages6
JournalNational Academy of Sciences. Proceedings
Volume107
Issue number52
Publication statusPublished - 28 Dec 2010

Keywords

  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase, Antimicrobial Cationic Peptides, Blotting, Western, Calcitriol, Cells, Cultured, Cytokines, Gene Expression, Humans, Interferon-gamma, Interleukin-4, Monocytes, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Steroid Hydroxylases, T-Lymphocytes, Th1 Cells, Th2 Cells, Toll-Like Receptor 1, Toll-Like Receptor 2, Vitamin D, Vitamin D3 24-Hydroxylase, beta-Defensins