Glycogen synthase kinase-3 negatively regulates anti-inflammatory interleukin-10 for lipopolysaccharide-induced iNOS/NO biosynthesis and RANTES production in microglial cells

Wei Ching Huang, Yee Shin Lin, Chi Yun Wang, Cheng Chieh Tsai, Hsiang Chi Tseng, Chia Ling Chen, Pei Jung Lu, Po See Chen, Li Qian, Jau Shyong Hong, Chiou Feng Lin

研究成果: Article同行評審

89 引文 斯高帕斯(Scopus)

摘要

The inflammatory effects of glycogen synthase kinase-3 (GSK-3) have been identified; however, the potential mechanism is still controversial. In this study, we investigated the effects of GSK-3-mediated interleukin-10 (IL-10) inhibition on lipopolysaccharide (LPS)-induced inflammation. Treatment with GSK-3 inhibitor significantly blocked LPS-induced nitric oxide (NO) production as well as inducible NO synthase (iNOS) expression in BV2 murine microglial cells and primary rat microglia-enriched cultures. Using an antibody array and enzyme-linked immunosorbent assay, we found that GSK-3-inhibitor treatment blocked LPS-induced upregulation of regulated on activation normal T-cell expressed and secreted (RANTES) and increased IL-10 expression. The time kinetics and dose-response relations were confirmed. Reverse transcription-polymerase chain reaction showed changes on the messenger RNA level as well. Inhibiting GSK-3 using short-interference RNA, and transfecting cells with dominant-negative GSK-3β, blocked LPS-elicited NO and RANTES expression but increased IL-10 expression. In contrast, GSK-3β overexpression upregulated NO and RANTES but downregulated IL-10 in LPS-stimulated cells. Treating cells with anti-IL-10 neutralizing antibodies to prevent GSK-3 from downregulating NO and RANTES showed that the anti-inflammatory effects are, at least in part, IL-10-dependent. The involvement of Akt, extracellular signal-regulated kinase, p38 mitogen-activated protein kinase and nuclear factor-κB that positively regulated IL-10 was demonstrated. Furthermore, inhibiting GSK-3 increased the nuclear translocation of transcription factors, that all important for IL-10 expression, including CCAAT/enhancer-binding protein beat (C/EBPβ), C/EBPδ, cAMP response binding element protein and NF-κB. Taken together, these findings reveal that LPS induces iNOS/NO biosynthesis and RANTES production through a mechanism involving GSK-3-mediated IL-10 downregulation.

原文English
頁(從 - 到)e275-e286
期刊Immunology
128
發行號1 PART 2
DOIs
出版狀態Published - 2009 九月

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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