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IL-20 Is Regulated by Hypoxia-Inducible Factor and Up-Regulated after Experimental Ischemic Stroke

Wei-Yu Chen^* and Ming-Shi Chang^1,*,

^* Institute of Basic Medical Sciences and Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan

IL-20, an IL-10 family member, is involved in various inflammatory diseases, such as psoriasis, rheumatoid arthritis, and atherosclerosis. We investigated whether hypoxia in vitro and an in vivo model of ischemic stroke would up-regulate IL-20 expression. In vitro, IL-20 expression increased in hypoxic HaCaT, HEK293 cells, chondrocytes, monocytes, and glioblastoma cells. Inhibition of hypoxia-inducible factor 1 inhibited CoCl₂-induced IL-20 expression. We identified two putative hypoxia response elements in the human il20 gene promoter. Promoter activity assays showed that CoCl₂ mimicked hypoxia-activated luciferase reporter gene expression. In vivo, experimental ischemic stroke up-regulated IL-20 in the sera and brain tissue of rats. IL-20 stained positively in glia-like cells in peri-infarcted lesions, but not in contralateral tissue. Administration of IL-20 mAb ameliorated ischemia-induced brain infarction of rats after experimental ischemic stroke. In vitro, RT-PCR analysis showed that glioblastoma cells, GBM8901, expressed IL-20 and its receptor subunits IL-20R1, IL-20R2, and IL-22R1. IL-20 induced cell proliferation in GBM8901 cells by activating the JAK2/STAT3 and ERK1/2 pathways. IL-20 also induced production of IL-1β, IL-8, and MCP-1 in GBM8901 cells. We conclude that IL-20 was responsive to hypoxia in vitro and in the ischemic stroke model and that up-regulation of IL-20 in the ischemic brain may contribute to brain injury.

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¹ Address correspondence and reprint requests to Prof. Ming-shi Chang, Department of Biochemistry and Molecular Biology, National Cheng Kung University, College of Medicine, Tainan 704, Taiwan. E-mail address: mschang{at}mail.ncku.edu.tw

² Abbreviations used in this paper: HIF-1, hypoxia-inducible factor 1; MCAO, middle cerebral artery occlusion; HRE, hypoxia response element; β-gal, β-galactosidase; 2ME2, 2-methoxy estradiol; MCA, middle cerebral artery; TTC, 2,3,5-triphenyltetrazolium chloride; GFAP, glial fibrillary acidic protein; TSS, transcriptional start site; MIF, migration inhibitory factor; 5' RACE, rapid amplification of 5' complementary DNA ends.

³ The online version of this article contains supplemental material.