Activation of human valvular fibroblasts by glucosyltransferases of viridans streptococci to induce chemotaxis of leukocytes
Date Issued
2007
Date
2007
Author(s)
Chang, Chia-Jung
DOI
zh-TW
Abstract
Streptococcus mutans is a member of viridans group streptococci and one of the opportunistic pathogens causing subacute infective endocarditis (IE). The major process in the pathogenesis of IE is initiated when pathogens circulating in the bloodstream colonize to damaged valves and then secrete virulence factors to induce a chronic inflammatory response. Glucosyltransferases (GTFs) of viridans streptococci are the important bacterial modulins and potent inducers of interleukin-6 (IL-6) synthesis and release from human PBMC and HUVEC. Because the heart valves were constituted primary by meshes of fibroblasts, we investigated the primary culture of valvular fibroblasts from heart transplant patients to study the immune response stimulated by GTFs and to define the mechanism of IE triggered by the viridans streptococci.
We reported that GTFs attached to human primary valvular fibroblasts triggered the release of IL-6, IL-8 and MCP-1, and enhanced the phosphorylation of AKT, MAPKs and IκB-α and the nuclear translocation of NF-κB. The increase in IL-6, IL-8 and MCP-1 was abrogated by addition of PI3K, MAPKs, and NF-κB inhibitors, suggesting that the up-regulation of IL-6, IL-8 and MCP-1 was mediated through PI3K, MAPKs, and NF-κB signaling pathways. We also demonstrated that valvular fibroblasts treated by GTFs promoted the chemotaxis and adhesion of monocytic cell lines. In addition, GTFs-stimulated valvular fibroblasts could induce the release of CXCR4-specific ligand to enhance the recruitment of T lymphocyte.
Because GTFs could stimulate human mononuclear cells to produce interleukin-1β(IL-1β), we hypothesized that the infiltration of GTFs-activated mononuclear cells could play a role in enhancing inflammatory response. We found that exogenous IL-1β could activate valvular fibroblasts, trigger the release of IL-6, IL-8 and MCP-1, and up-regulate the expression of ICAM-1. In addition, IL-1β-stimulated fibroblasts could promote the chemotaxis and adhesion of monocytic cell lines.
Taken together, these results indicate that GTFs could induce the synthesis and release of inflammatory cytokine and chemokine to trigger the infiltration of leukocytes a characteristic in the pathogenesis of IE caused by viridans group streptococci. Furthermore, GTFs-activated mononuclear cells could secrete IL-1β to further stimulate valvular fibroblasts and sustain the formation of chronic endocardial inflammation.
Subjects
轉糖鏈球菌
葡萄糖傳遞酶
人類瓣膜纖維母細胞
趨化作用
Streptococcus mutans
glucosyltransferase
human valvular fibroblasts
chemotaxis
Type
other
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