Hypoxia-induced IL-18 increases hypoxia-inducible factor-1alpha expression through a Rac1-dependent NF-kappaB 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-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.
Kim
Jeongki
J
Stem Cell Research Center, Korea Research Institute of Bioscience and Biotechnology, Yusong, Daejon 305-333, Republic of Korea.
Shao
Yan
Y
Kim
Sang Yong
SY
Kim
Seyl
S
Song
Hyun Keun
HK
Jeon
Jun Ho
JH
Suh
Hyun Woo
HW
Chung
Jin Woong
JW
Yoon
Suk Ran
SR
Kim
Young Sang
YS
Choi
Inpyo
I
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*
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