| Summary: | 博士 === 國立成功大學 === 基礎醫學研究所 === 97 === IL-20, an IL-10 family member, is involved in various inflammatory diseases, such as psoriasis, rheumatoid arthritis, intervertebral disc herniation, and renal diseases. Atherosclerosis is a chronic inflammatory disease with immune-cell infiltration. Various cytokines and chemokines have been characterized as pro- or anti-atherogenic factors. However, the association between IL-20 and atherosclerosis is undetermined. Therefore, we sought to investigate whether IL-20 is associated with atherosclerosis. We examined the expression of IL-20 and its receptor complex IL-20R1/IL-20R2 in atherosclerotic lesions of humans and mice using immunohistochemical staining. IL-20 was expressed in macrophage-rich areas. Both IL-20 and IL-20R1/IL-20R2 were expressed by endothelial cells lining the intimal microvessels, vasa vasorum, but rarely in non-atherosclerotic arteries. IL-20 transcripts increased in hypoxic monocytes and monocytes treated with oxidized low-density lipoprotein. The expression of IL-20R1 and IL-20R2 was also upregulated by HUVECs in response to hypoxic treatment. IL-20 upregulated the transcripts of CXCL9 and CXCL11 in HUVEC cells. Furthermore, in vivo administration of IL-20 expression vector using intramuscular electroporation promoted atherosclerosis in Apolipoprotein E-deficient mice. Therefore, IL-20 may act as a pro-atherogenic factor. In this study, we also investigated whether hypoxia in vitro and an in vivo model of ischemic stroke would upregulate IL-20 expression. In vitro, IL-20 expression increased in hypoxic HaCaT , HEK293 cells, chondrocytes, monocytes and glioblastoma cells. Inhibiting HIF-1alpha inhibited CoCl2-induced IL-20 expression. We identified two putative hypoxia response elements in human il20-gene promoter. Promoter activity assays showed that CoCl2-mimicked hypoxia activated luciferase reporter-gene expression. In vivo, experimental ischemic stroke upregulated 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 monoclonal antibody ameliorated ischemia-induced brain infarction of rats after experimental ischemic stroke. In vitro, RT-PCR analysis showed that glioblastoma cells GBM8901 cells 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-1beta, 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 upregulation of IL-20 in the ischemic brain may contribute to brain injury. In summary, IL-20 is a pro-inflammatory cytokine and regulated by hypoxia. The upregulation of IL-20 may contribute to the pathogenesis of atherosclerosis plaque progression and brain injury after ischemic stroke.
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