Role of vitamin D locally at the inflammation site – example based on Mtb infection. 1,25-(OH)2D, the active form of vitamin D produced by macrophage-CYP27B1 at the inflammation site, has many local actions leading to a negative feedback loop avoiding macrophage overstimulation. 1,25-(OH)2D reduces T helper (Th1) lymphocyte-mediated macrophage activation, (a) by activating regulatory T-cells (Treg) which inhibit the activation of Th1 lymphocytes by antigen-presenting cells (APC) , (b) by directly inhibiting activation of Th1 lymphocytes and thus their interferon-γ (IFN-γ) production, and (c) by preventing antigen presentation by APC to Th1 lymphocytes . 1,25-(OH)2D acts also directly on macrophages (d) by reducing expression of Toll-like receptor (TLR) to Mycobacterium tuberculosis (Mtb) , and (e) by inducing intracellular Mtb destruction via the cathelicidin-mediated system. If macrophages are overstimulated, high local level of 1,25-(OH)2D could lead to systemic spill over and thus hypercalcemia, as has been described in Mtb-IRIS , since no systemic negative feedback by the parathyroid axis exists on macrophage-1,25-hydroxylase (CYP27B1) .