The lumen of the colon is almost anoxic whereas the oxygen supply of mucosal and submucosal layers is comprehensive. In the healthy organ epithelial tips show hypoxic features which spread to the basal epithelium, mucosa, and submucosa whenever inflammatory events disrupt the epithelial barrier. Attracted immune cells have to function in a setting of inflammatory hypoxia. How crucial the gene transcription regulators hypoxia-inducible factors (HIFs) hereby drive immune cell function will be the topic of this talk. Mice (C57Bl/6 background) with a conditional knockout for HIF-1α in either cells of the myeloid lineage (lyz2-cre) or in dendritic cells (Itgam-cre) and with a double knockout of HIF-1α and HIF-2α in myeloid cells have been used in a model of DSS (dextransodiumsulfate)-induced colitis. Mice have been treated with strain specific DSS concentrations to ensure similar extent of inflammation, details are indicated in the results. During the treatment, we assessed weight loss and disease activity index (containing weight loss, stool consistency, and rectal bleeding) of the mice. Colon and mesenteric lymph nodes have been excised from sacrificed mice and analyzed for shortening and weight, mRNA has been isolated and changes in gene expression have been analyzed with qPCR. In addition, histological analysis of the colon was performed. Data have been analyzed by one way or two way ANOVA plus post-test, P<0.05 has been considered significant. Loss of HIF-1α hereby reduced signs of colon inflammation (measured by DAI, disease activity index of histologic analysis of the colon) in lyz2-cre+/-/HIF-1α+f/+f mice (DAI of control mice: 8.7 ± 1.2; HIF-1α DF x lyz-2-cre: 6.8 ± 0.7; 2.5 % DSS for 6 days; n= 5-6) due to reduced numbers of proinflammatory macrophages, dendritic cells, and Th17 positive T cells in the inflamed colon. This was consistent with a reduced and delayed gene expression of pro- and anti-inflammatory cytokines such as tnfa, ifng, and il-10. Parts of these findings could be reversed by additional knockout of HIF-2α as lyz2-cre+/-/HIF-1α+f/+f/ HIF-2α+f/+f mice do not show a DAI different from wildtype mice (7.6 ± 0.7). In contrast, mice lacking HIF-1α in dendritic cells lost significantly more weight during acute colitis (86.33 ± 1.39 for wt, 81.35 ± 1.37 for ko at day 7 of treatment). Interestingly, knockout of HIF-1α in dendritic cells did not alter overall colon inflammation (DAI of control mice: 10.8 ± 0.5, itgam-cre+/-/HIF-1α+f/+f: 10.9 ± 0.4; 3 % DSS for 7 days; n=9-14). Bone marrow derived dendritic cells lacking HIF-1α show a significantly reduced ability to produce the anti-inflammatory cytokine IL-10 in response to inflammatory stimulation. This (amongst other factors) might lead to a diminished stimulation of regulatory T cells in the mesenteric lymph nodes of itgam-cre+/-/HIF-1α+f/+f mice which was assessed by foxp3 and ox40 mRNA quantification. Furthermore, gut homing of regulatory T cells was impaired in these mice which resulted in a dominantly pro-inflammatory setting with activated dendritic cells secreting proinflammatory cytokines such as IL-6 and IL-23 and a missing counter-regulation by anti-inflammatory Tregs. Knockout of HIF-1α in two different proportions of the cellular innate immune defense results in completely diverse outcome in a mouse model of acute DSS colitis. Knockdown of HIF-2α in addition to HIF-1α seemed to reverse HIF-1 driven effects. Our findings begin to shed some light on the complexity of inflammatory hypoxia and the role of HIF complexes in colitis.