| First Author | Die L | Year | 2012 |
| Journal | Mol Immunol | Volume | 52 |
| Issue | 1 | Pages | 38-49 |
| PubMed ID | 22580404 | Mgi Jnum | J:188169 |
| Mgi Id | MGI:5439257 | Doi | 10.1016/j.molimm.2012.04.005 |
| Citation | Die L, et al. (2012) Glycogen synthase kinase-3 beta inhibitor suppresses Porphyromonas gingivalis lipopolysaccharide-induced CD40 expression by inhibiting nuclear factor-kappa B activation in mouse osteoblasts. Mol Immunol 52(1):38-49 |
| abstractText | 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-3beta (GSK-3beta) inhibitors; however, their effect on osteoblasts remains largely unclear. In the present study, we showed that treatment with SB216763, a highly specific GSK-3beta 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-alpha and IL-1beta, in the Porphyromonas gingivalis-lipopolysaccharide (LPS)-stimulated murine osteoblastic-like MC3T3-E1 cells. Furthermore, inhibition of GSK-3beta remarkably represses the LPS-induced activation of the nuclear factor kappa B (NF-kappaB) signaling pathway by suppressing IkappaBalpha phosphorylation, NF-kappaBp65 nuclear translocation, and NF-kappaBp65 DNA binding activity. Closer investigation by immunoprecipitation assay revealed that beta-catenin can physically interact with NF-kappaBp65. The negative regulation effect of GSK-3beta inhibitor on CD40 expression is mediated through beta-catenin, for siRNA of beta-catenin attenuated the GSK-3beta inhibitor-induced repression of NF-kappaB 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-3beta inhibitor prevents the LPS-induced CD40 expression on osteoblasts and provide supportive evidence of the potential role of GSK-3beta inhibitors in suppressing the immune function of osteoblasts in inflammatory bone diseases. |
