1,25-DihydroxyVitamin D₃ (1,25(OH)₂D₃), a molecule with well-known actions in bone and mineral homeostasis, also plays a role in the immune system. Indeed, the receptor for 1,25(OH)₂D₃ is found in most immune cells and important immunological effects have been described in vitro, reflected by its capacity to prevent autoimmunity and to prolong graft survival. The aim of this study was to elucidate the intracellular pathways used by the immune system to regulate 1,25(OH)₂D₃ production. Therefore we studied the regulation of 25-hydroxyvitamin-d-1α-hydroxylase (1α hydroxylase) in THP1 cells by IFNγ, demonstrating that its induction is highly dependent on the activation/differentiation by PMA and occurred at a late time point (140-fold at 72h, P<0.05). Complete inhibition with actinomycin D indicated that the observed induction was, at least in part, a transcriptional event. Dose-dependent inhibition with cycloheximide demonstrated that the induction was dependent on “de novo” protein synthesis, a finding that correlates with the late time point of up-regulation. The data presented indicate a role for 1,25(OH)₂D₃, activated by 1α hydroxylase, as a late down-tapering signal in the immune cascade.