Hypoxia-induced IL-18 increases hypoxia-inducible factor-1α expression through a Rac1-dependent NF-κB pathway

Interleukin-18 (IL-18) plays pivotal roles in linking inflammatory immune responses and tumor progression and metastasis, yet the manner in which this occurs remains to be sufficiently clarified. Here we report that hypoxia induces the transcription and secretion of IL-18, which subsequently induces the expression of hypoxia-inducible factor-1 alpha(HIF-1 alpha). Mechanistically, IL-18 induces HIF-1 alpha through the activity of the GTPase Rac1, which inducibly associates with the IL-18 receptor beta (IL-18R beta) subunit, via a PI3K-AKT-NF-kappa B-dependent pathway. Importantly, the knockdown of the IL-18R beta subunit inhibited IL-18-driven tumor cell metastasis. Collectively, these findings demonstrate a feed-forward pathway in HIF-1 alpha-mediated tumor progression, in which the induction of IL-18 by hypoxia or inflammatory cells augments the expression of both HIF-1 alpha and tumor cell metastasis.