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

• Published in: Molecular biology of the cell Vol. 19; no. 2; p. 433
• Main Authors: Kim, Jeongki, Shao, Yan, Kim, Sang Yong, Kim, Seyl, Song, Hyun Keun, Jeon, Jun Ho, Suh, Hyun Woo, Chung, Jin Woong, Yoon, Suk Ran, Kim, Young Sang, Choi, Inpyo
• Format: Journal Article
• Language: English
• Published: United States 01-02-2008
• Subjects: Animals; Cell Hypoxia - drug effects; Cell Line; Gene Expression Regulation - drug effects; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Interleukin-18 - genetics; Interleukin-18 - metabolism; Interleukin-18 - pharmacology; Mice; Neoplasm Metastasis; NF-kappa B - metabolism; Phosphatidylinositol 3-Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; rac1 GTP-Binding Protein - metabolism; Reactive Oxygen Species - metabolism; Receptors, Interleukin-18 - metabolism; Signal Transduction - drug effects; Transcription, Genetic - drug effects
• ISSN: 1939-4586

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-1alpha (HIF-1alpha). Mechanistically, IL-18 induces HIF-1alpha through the activity of the GTPase Rac1, which inducibly associates with the IL-18 receptor beta (IL-18Rbeta) subunit, via a PI3K-AKT-NF-kappaB-dependent pathway. Importantly, the knockdown of the IL-18Rbeta subunit inhibited IL-18-driven tumor cell metastasis. Collectively, these findings demonstrate a feed-forward pathway in HIF-1alpha-mediated tumor progression, in which the induction of IL-18 by hypoxia or inflammatory cells augments the expression of both HIF-1alpha and tumor cell metastasis.