The alkaline pH-activated K2P5.1 K+ channel contributes to the setting of the resting potential and the control of Ca2+ signaling. K2P5.1 is up-regulated in CD4+ T cells from patients of autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. We have reported that K2P5.1 is up-regulated in inflammatory CD4+ T (Th1) cells of inflammatory bowel disease (IBD) model mice and that K2P5.1 is a possible therapeutic target for IBD. However, it remains unclear the mechanisms underlying up-regulation of K2P5.1 in Th1 cells. We recently showed that Ca2+-activated K+ channel KCa3.1 was post-transcriptionally regulated by histone deacetylases (HDACs) in Th1 cells of IBD model mice. Present study showed no changes in the expression levels of K2P5.1 by HDAC inhibitor treatment in CD4+ cells. Hypoxia underlies the polarization of the Th1 lymphocytes in inflamed tissues. Up-regulation of hypoxia-inducible factor (HIF)-1α was found in CD4+ T cells of IBD model mice. Hypoxia (1.5% O2) for 24 hr increased the expression levels of K2P5.1 in mice CD4+ thymocytes. These results suggest that K2P5.1 may be up-regulated in Th1 cells of IBD model through HIF-1α-mediated signaling pathway.