title: Hypoxia-induced IL-18 increases hypoxia-inducible factor-1alpha expression through a Rac1-dependent NF-kappaB pathway.
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.
authors.affiliation: Stem Cell Research Center, Korea Research Institute of Bioscience and Biotechnology, Yusong, Daejon 305-333, Republic of Korea.
authors.forename: Jeongki
authors.initials: J
authors.lastname: Kim
authors.forename: Yan
authors.initials: Y
authors.lastname: Shao
authors.forename: Sang Yong
authors.initials: SY
authors.lastname: Kim
authors.forename: Seyl
authors.initials: S
authors.lastname: Kim
authors.forename: Hyun Keun
authors.initials: HK
authors.lastname: Song
authors.forename: Jun Ho
authors.initials: JH
authors.lastname: Jeon
authors.forename: Hyun Woo
authors.initials: HW
authors.lastname: Suh
authors.forename: Jin Woong
authors.initials: JW
authors.lastname: Chung
authors.forename: Suk Ran
authors.initials: SR
authors.lastname: Yoon
authors.forename: Young Sang
authors.initials: YS
authors.lastname: Kim
authors.forename: Inpyo
authors.initials: I
authors.lastname: Choi
mesh_terms: D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D020382:Interleukin-18 / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D009362:Neoplasm Metastasis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D053724:Receptors, Interleukin-18 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020382:Interleukin-18; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D053724:Receptors, Interleukin-18; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020830:rac1 GTP-Binding Protein