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

• DOI: 10.1016/j.imbio.2012.07.018
• Publication Date: 2012-08-01T21:20:43Z
• Authors: Hannelie Korf; Mathias Wenes; Benoit Stijlemans; Tatiana Takiishi; Sofie Robert; Michela Miani; Decio L. Eizirik; Conny Gysemans; Chantal Mathieu
• Keywords: Inflammation -- immunology -- metabolism; 0301 basic medicine; Nitric Oxide Synthase Type II -- immunology -- metabolism; Macrophage; type 1 diabetes; Cells; T-Lymphocytes; Nitric Oxide Synthase Type II; Inbred C57BL; Lymphocyte Activation; Mice; 03 medical and health sciences; Calcitriol; Mice, Inbred NOD; Receptors; Diabetes Mellitus; Animals; Vitamin D; Cells, Cultured; Inflammation; T-Lymphocytes -- immunology -- metabolism; Cultured; Animal; Interleukin-12 Subunit p40; Tumor Necrosis Factor-alpha; Interleukin-12 Subunit p40 -- immunology -- metabolism; Macrophages; Interleukin-10 -- immunology -- metabolism; Sciences bio-médicales et agricoles; Lymphocyte Activation -- immunology; Macrophages -- immunology -- metabolism; Interleukin-10; 3. Good health; Mice, Inbred C57BL; Tumor Necrosis Factor-alpha -- immunology -- metabolism; Disease Models, Animal; CXC -- immunology -- metabolism; Type 1 diabetes; Diabetes Mellitus, Type 1; Type 1 -- immunology -- metabolism; inflammation; Disease Models; Calcitriol -- immunology -- metabolism; Inbred NOD; Receptors, Calcitriol; Female; Chemokines; Chemokines, CXC

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.