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Vol. 19, Issue 2, 433-444, February 2008

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Hypoxia-induced IL-18 Increases Hypoxia-inducible Factor-1 Expression through a Rac1-dependent NF-B Pathway

Jeongki Kim^*,,, 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, and Inpyo Choi^*

*Stem Cell Research Center, Korea Research Institute of Bioscience and Biotechnology, Yusong, Daejon 305-333, Republic of Korea; Daedeok Valley Integrated Bio-resources Center and Department of Biochemistry, Chungnam National University, Daejon 305-764, Republic of Korea; and ^||Department of Anatomy, Inje University College of Medicine, Pusan 614-735, Republic of Korea

Submitted February 28, 2007; Revised September 26, 2007; Accepted November 5, 2007
Monitoring Editor: John Cleveland

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

These authors contributed equally to this work.

Address correspondence to: Inpyo Choi (ipchoi{at}kribb.re.kr)

Abbreviations used: EMSA, electrophoretic mobility shift assay; HIF-1, hypoxia inducible factor-1; IL-18, interleukin-18; IL-18 Rβ, interleukin-18 receptor β; MAPK, mitogen-activated protein kinase; NAC, N-acetyl-L-cysteine; PI3K, phosphatidylinositol-3-kinase; ROS, reactive oxygen species; VEGF, vascular endothelial growth factor.

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