| Abstrakt: |
1α,25-dihydroxyvitamin D3(1α,25(OH)2D3), the activated vitamin D3hormone, is a key regulator of calcium homeostasis and thereby indispensable for bone metabolism. In addition, 1α,25(OH)2D3is known to mediate predominantly immunosuppressive responses in vitro and in vivo. It has been demonstrated that macrophages can produce 1α,25(OH)2D3on activation with interferon γ (IFN-γ), although little is understood about the biologic significance of this response. We show here that 1α,25(OH)2D3can selectively suppress key effector functions of IFN-γ–activated macrophages. Among these are the suppression of listericidal activity, the inhibition of phagocyte oxidase-mediated oxidative burst, and the suppression of important IFN-γ–induced genes, including Ccl5, Cxcl10, Cxcl9, Irf2, Fcgr1, Fcgr3, and Tlr2. The deactivation of IFN-γ–stimulated macrophages is dependent on a functional vitamin D receptor and 1α,25(OH)2D3acts specifically on IFN-γ–activated macrophages, whereas the steroid has no effects on resting macrophages. Therefore, the 1α,25(OH)2D3–mediated suppression of macrophage functions is distinct from previously described macrophage deactivation mechanisms. In conclusion, our data indicate that the production of 1α,25(OH)2D3by IFN-γ–stimulated macrophages might be an important negative feedback mechanism to control innate and inflammatory responses of activated macrophages. |
