Inflammatory stimulation and hypoxia cooperatively activate HIF-1{alpha} in bronchial epithelial cells: involvement of PI3K and NF-{kappa}B.
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-1α. Recent studies have demonstrated that non-hypoxic stimuli can also activate HIF-1α in a cell-specific manner. Here, we demonstrate that stimulation of BEAS-2B cells and primary human bronchial epithelial cells by proinflammatory cytokines TNFα/IL-4 strongly induced expression and transcriptional activity of HIF-1α under normoxic conditions and amplified hypoxic HIF-1α activation. TNFα/IL-4 stimulated de novo HIF-1α gene transcription and translation rather than affected HIF-1α protein degradation and mRNA decay process. The activation of HIF-1α by TNFα/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, TNFα/IL-4 also activated NF-κB, whereas blocking of NF-κB by an inhibitor or silencing NF-κB subunit p65 attenuated HIF-1α activation by TNFα/IL-4. We also found the collaborative induction of VEGF, a potent angiogenic factor required for airway remodeling, by TNFα/IL-4 and hypoxia partially via HIF-1α pathway in BEAS-2B cells. This study reports the previously unsuspected collaborative regulation of HIF-1α by TNFα/IL-4 and hypoxia in bronchial epithelial cells partially via PI3K-mTOR and NF-κB 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.
Department of Anesthesiology, Shanghai Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, China.
Hong
H
Jiang
Ye Sen
YS
Zhu
Hui
H
Xu
Yu
Y
Sun
Qi Fang
QF
Li
D001483:Base Sequence; D001980:Bronchi / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015687:Cell Hypoxia / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism* / Q000494:pharmacology; D015847:Interleukin-4 / Q000378:metabolism / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018836:Inflammation Mediators; D015847:Interleukin-4; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D058570:TOR Serine-Threonine Kinases; D014409:Tumor Necrosis Factor-alpha; C497442:HIF1A protein, human; C546842:MTOR protein, human