1,25-Dihydroxyvitamin D3 curtails the inflammatory and T cell stimulatory capacity of macrophages through an IL-10-dependent mechanism.

Abstract

The vitamin D receptor (VDR) is a hormone nuclear receptor regulating bone and calcium homeostasis. Studies revealing the expression of VDR on immune cells point toward a role for VDR-dependent signaling pathways in immunity. Here we verified the ability of the natural VDR ligand, 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) to interfere in inflammatory and T cell stimulatory capacity of macrophages, in particular within a chronic inflammatory disease features of experimental type 1 diabetes (T1D). We demonstrated that VDR is constitutively expressed in macrophages and both the levels of VDR and its downstream targets, are clearly induced by 1,25(OH)(2)D(3). In control mice, macrophage programming with 1,25(OH)(2)D(3) partially abrogated the activation-provoked expression of IL-12p40, TNFα and iNOS as well as the effector T cell-recruiting chemokines, CXCL9, CXCL10 and CXCL11. Targeting VDR signaling in macrophages counteracted their T-cell stimulatory ability despite essentially unaltered expression of antigen-presenting and costimulatory molecules. Furthermore, even in non-obese diabetic (NOD) mice, where macrophages/monocytes featured a heightened responsiveness toward danger signals and a superior T cell stimulatory capacity, 1,25(OH)(2)D(3) successfully curtailed these basic macrophage-mediated functions. Interestingly, the inhibitory action of the active compound was associated with an IL-10-dependent mechanism since 1,25(OH)(2)D(3)-treatment of IL-10-deficient macrophages failed to reproduce the characteristic repression on inflammatory mediators or T cell proliferation. Combined, these results highlight the possible therapeutic applicability of this natural immunomodulator, due to its ability to counteract macrophage inflammatory and T cell-activating pathways.

• Authors: Hannelie Korf, Mathias Wenes, Benoit Stijlemans, Tatiana Takiishi, Sofie Robert, Michela Miani, Decio L Eizirik, Conny Gysemans, Chantal Mathieu
• Journal: Immunobiology (Immunobiology) Vol. 217 Issue 12 Pg. 1292-300 (Dec 2012) ISSN: 1878-3279 [Electronic] Netherlands
• PMID: 22944250 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier GmbH. All rights reserved.

Chemical References

• Chemokines, CXC
• IL10 protein, mouse
• Interleukin-12 Subunit p40
• Receptors, Calcitriol
• Tumor Necrosis Factor-alpha
• Interleukin-10
• Nitric Oxide Synthase Type II
• Nos2 protein, mouse
• Calcitriol

Topics

• Animals
• Calcitriol (immunology, metabolism)
• Cells, Cultured
• Chemokines, CXC (immunology, metabolism)
• Diabetes Mellitus, Type 1 (immunology, metabolism)
• Disease Models, Animal
• Female
• Inflammation (immunology, metabolism)
• Interleukin-10 (immunology, metabolism)
• Interleukin-12 Subunit p40 (immunology, metabolism)
• Lymphocyte Activation (immunology)
• Macrophages (immunology, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Inbred NOD
• Nitric Oxide Synthase Type II (immunology, metabolism)
• Receptors, Calcitriol (immunology, metabolism)
• T-Lymphocytes (immunology, metabolism)
• Tumor Necrosis Factor-alpha (immunology, metabolism)