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

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

  • Mol Biol Cell. 2008 Feb;19(2):433-44. doi: 10.1091/mbc.e07-02-0182.
Jeongki Kim 1 Yan Shao Sang Yong Kim Seyl Kim Hyun Keun Song Jun Ho Jeon Hyun Woo Suh Jin Woong Chung Suk Ran Yoon Young Sang Kim Inpyo Choi
Affiliations

Affiliation

  • 1 Stem Cell Research Center, Korea Research Institute of Bioscience and Biotechnology, Yusong, Daejon 305-333, Republic of Korea.
Abstract

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.

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