Glycogen synthase kinase-3 beta inhibitor suppresses Porphyromonas gingivalis lipopolysaccharide-induced CD40 expression by inhibiting nuclear factor-kappa B activation in mouse osteoblasts
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- 作者：Liu Die llmld@126.com ; Peng Yan 22652994@qq.com ; Zhai Jun Jiang zcole19841023@163.com ; Teng Min Hua tengminhua@163.com ; Wen Cai iamwencai@163.com ; Liang Xing ; xingliangdent@vip.163.com
- 关键词：LPS ; lipopolysaccharide ; SB216763 ; 3-(2 ; 4-dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2 ; 5-dione ; Wnt ; Wingless ; GSK-3¦Â ; glycongen synthase kinase-3 beta ; APC ; adenomatous polyposis coli ; Tcf/Lef ; T-cell factor protein and lymphoid enhancer fact
- 刊名：Molecular Immunology
- 出版年：2012
- 出版时间：August, 2012
- 年：2012
- 卷：52
- 期：1
- 页码：38-49
- 全文大小：1793 K
文摘
Bone-forming osteoblasts have been recently reported capable of expressing the critical co-stimulatory molecule CD40 upon exposure to bacterial infection, which supports the unappreciated role of osteoblasts in modulating bone inflammation. Recent studies highlight the anti-inflammatory potential of glycogen synthase kinase-3¦Â (GSK-3¦Â) inhibitors; however, their effect on osteoblasts remains largely unclear. In the present study, we showed that treatment with SB216763, a highly specific GSK-3¦Â inhibitor, resulted in a dose-dependent decrease in the mRNA and protein expression of CD40, as well as production of pro-inflammatory cytokines IL-6, TNF-¦Á and IL-1¦Â, in the Porphyromonas gingivalis-lipopolysaccharide (LPS)-stimulated murine osteoblastic-like MC3T3-E1 cells. Furthermore, inhibition of GSK-3¦Â remarkably represses the LPS-induced activation of the nuclear factor kappa B (NF-¦ÊB) signaling pathway by suppressing I¦ÊB¦Á phosphorylation, NF-¦ÊBp65 nuclear translocation, and NF-¦ÊBp65 DNA binding activity. Closer investigation by immunoprecipitation assay revealed that ¦Â-catenin can physically interact with NF-¦ÊBp65. The negative regulation effect of GSK-3¦Â inhibitor on CD40 expression is mediated through ¦Â-catenin, for siRNA of ¦Â-catenin attenuated the GSK-3¦Â inhibitor-induced repression of NF-¦ÊB activation and, consequently, the expression of CD40 and production of pro-inflammatory cytokines in LPS-stimulated MC3T3-E1 cells. Thus our results elucidate the molecular mechanisms whereby GSK-3¦Â inhibitor prevents the LPS-induced CD40 expression on osteoblasts and provide supportive evidence of the potential role of GSK-3¦Â inhibitors in suppressing the immune function of osteoblasts in inflammatory bone diseases.