Enhanced interferon-gamma gene expression in T Cells and reduced ovalbumin-dependent lung eosinophilia in hypoxia-inducible factor-1-alpha-deficient mice.

BACKGROUND

There is growing evidence that hypoxia-inducible transcription factors are involved in the pathophysiology of asthma. Hypoxia-inducible factor-1alpha (HIF-1alpha) in particular controls the expression of many hypoxia regulated genes, but whether HIF-1alpha directly contributes to allergen-driven immune responses is not known.

METHODS

Partially HIF-1alpha-deficient mice (HIF-1alpha(+/-)) 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-gamma secretion was significantly higher in anti-CD3 plus anti-CD28 stimulated CD4+ T cells obtained from HIF-1alpha(+/-) mice compared to wild-type controls. HIF-1alpha(+/-) mice were protected from lung eosinophilia 72 h after allergen challenge, in association with enhanced secretion of interferon-gamma in recall responses of splenocytes.

CONCLUSIONS

HIF-1alpha contributes to allergic immune responses and lung eosinophilia in a mouse model of asthma.