Enhanced Interferon-γ Gene Expression in T Cells and Reduced Ovalbumin-Dependent Lung Eosinophilia in Hypoxia-Inducible Factor-1-α-Deficient Mice

Background: There is growing evidence that hypoxia-inducible transcription factors are involved in the pathophysiology of asthma. Hypoxia-inducible factor-1α (HIF-1α) in particular controls the expression of many hypoxia regulated genes, but whether HIF-1α directly contributes to allergen-driven immune responses is not known. Methods: Partially HIF-1α-deficient mice (HIF-1α^+/–) or wild-type littermate controls were used in all experiments. Spleen CD4+ T cells were stimulated with anti-CD3 plus anti-CD28 antibodies and cytokine secretion was measured in vitro. Mice were sensitized by intraperitoneal injection of ovalbumin (Ova) plus alum, and then challenged by intranasal Ova followed by bronchoalveolar lavage (BAL) and isolation of spleen cells. BAL cells were counted and the differential determined using cytospin, and splenocytes were incubated with Ova to measure recall cytokine production. Results: Interferon-γ secretion was significantly higher in anti-CD3 plus anti-CD28 stimulated CD4+ T cells obtained from HIF-1α^+/– mice compared to wild-type controls. HIF-1α^+/– mice were protected from lung eosinophilia 72 h after allergen challenge, in association with enhanced secretion of interferon-γ in recall responses of splenocytes. Conclusions: HIF-1α contributes to allergic immune responses and lung eosinophilia in a mouse model of asthma.