Inflammatory stimulation and hypoxia cooperatively activate HIF-1α in bronchial epithelial cells: involvement of PI3K and NF-κB

Jiang H, Zhu YS, Xu H, Sun Y, Li QF. Inflammatory stimulation and hypoxia cooperatively activate HIF-1 alpha in bronchial epithelial cells: involvement of PI3K and NF-kappa B. Am J Physiol Lung Cell Mol Physiol 298: L660-L669, 2010. First published February 5, 2010; doi: 10.1152/ajplung.00394.2009.-The transcription factor hypoxia-inducible factor (HIF)-1 plays a central physiological role in oxygen and energy homeostasis, and is activated during hypoxia by stabilization of the subunit HIF-1 alpha. Recent studies have demonstrated that non-hypoxic stimuli can also activate HIF-1 alpha in a cell-specific manner. Here, we demonstrate that stimulation of BEAS-2B cells and primary human bronchial epithelial cells by proinflammatory cytokines TNF alpha/IL-4 strongly induced expression and transcriptional activity of HIF-1 alpha under normoxic conditions and amplified hypoxic HIF-1 alpha activation. TNF alpha/IL-4 stimulated de novo HIF-1 alpha gene transcription and translation rather than affected HIF-1 alpha protein degradation and mRNA decay process. The activation of HIF-1 alpha by TNF alpha/IL-4 was countered by the phosphoinositol 3-kinase (PI3K) inhibitor LY-294002 and rapamycin, an antagonist of mammalian target of rapamycin (mTOR), but not by inhibition of the MAPK pathway. In line, TNF alpha/IL-4 also activated NF-kappa B, whereas blocking of NF-kappa B by an inhibitor or silencing NF-kappa B subunit p65 attenuated HIF-1 alpha activation by TNF alpha/IL-4. We also found the collaborative induction of VEGF, a potent angiogenic factor required for airway remodeling, by TNF alpha/IL-4 and hypoxia partially via HIF-1 alpha pathway in BEAS-2B cells. This study reports the previously unsuspected collaborative regulation of HIF-1 alpha by TNF alpha/IL-4 and hypoxia in bronchial epithelial cells partially via PI3K-mTOR and NF-kappa B pathway, and thereby will lead to the elucidation of the importance of HIF-1 in integrating inflammatory and hypoxic response in the pathogenesis of airway diseases.