{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T00:18:01Z","timestamp":1793146681945,"version":"4.5.0"},"reference-count":54,"publisher":"American Physiological Society","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Lung Cellular and Molecular Physiology"],"published-print":{"date-parts":[[2010,5]]},"abstract":"<jats:p>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\u03b1. Recent studies have demonstrated that non-hypoxic stimuli can also activate HIF-1\u03b1 in a cell-specific manner. Here, we demonstrate that stimulation of BEAS-2B cells and primary human bronchial epithelial cells by proinflammatory cytokines TNF\u03b1\/IL-4 strongly induced expression and transcriptional activity of HIF-1\u03b1 under normoxic conditions and amplified hypoxic HIF-1\u03b1 activation. TNF\u03b1\/IL-4 stimulated de novo HIF-1\u03b1 gene transcription and translation rather than affected HIF-1\u03b1 protein degradation and mRNA decay process. The activation of HIF-1\u03b1 by TNF\u03b1\/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\u03b1\/IL-4 also activated NF-\u03baB, whereas blocking of NF-\u03baB by an inhibitor or silencing NF-\u03baB subunit p65 attenuated HIF-1\u03b1 activation by TNF\u03b1\/IL-4. We also found the collaborative induction of VEGF, a potent angiogenic factor required for airway remodeling, by TNF\u03b1\/IL-4 and hypoxia partially via HIF-1\u03b1 pathway in BEAS-2B cells. This study reports the previously unsuspected collaborative regulation of HIF-1\u03b1 by TNF\u03b1\/IL-4 and hypoxia in bronchial epithelial cells partially via PI3K-mTOR and NF-\u03baB 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.<\/jats:p>","DOI":"10.1152\/ajplung.00394.2009","type":"journal-article","created":{"date-parts":[[2010,2,6]],"date-time":"2010-02-06T02:09:51Z","timestamp":1265422191000},"page":"L660-L669","source":"Crossref","is-referenced-by-count":63,"title":["Inflammatory stimulation and hypoxia cooperatively activate HIF-1\u03b1 in bronchial epithelial cells: involvement of PI3K and NF-\u03baB"],"prefix":"10.1152","volume":"298","author":[{"given":"Hong","family":"Jiang","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 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