| Summary: | 博士 === 國立臺灣大學 === 微生物學研究所 === 94 === Infective endocarditis (IE), a microbial infection in the heart valves, is characterized by vegetation formation and chronic endocardial inflammation. In the present study, we examined the role of glucosyltransferases (GTFs) found in viridans streptococci-induced infective endocarditis. GTFs were discovered in several IE-inducing streptococcal species, and presented as either the bacterial surface or extracellular enzyme, to synthesize glucan that cause bacterial aggregation and biofilm formation on tooth surfaces. GTFs were also identified to be modulins of IL-6 production in monocytes of human or rat. When treated on HUVEC, both bacteria-bound and -free GTFs could induce IL-6 and adhesion molecule expression through NF-kB activation. Activated endothelial cells enhance adhesion of monocytes and such adhesion can also be achieved by treating the cells with a mixture containing IL-6 and IL-6Rα. Furthermore, we demonstrate that GTF is detected in situ and induces IL-6 synthesis during acute phase of S. mutans-induced rat experimental endocarditis. In clinical specimens from viridans streptococci induced endocarditis, secretion of pro-inflammatory cytokines was detected on valvular, neocapillary endothelial cells, infiltrated macrophages and cardiac fibroblasts. Cardiac fibroblasts cultured in vitro can be activated synergistically by IL-1β and TNF-α, released from GTF-activated monocytes, to release MCP-1. Taken together, we propose a mechanism for endocardial inflammation during IE for recruitment and retention of monocytes, the former may be activated by bacterial modulins on endothelial lining, while, the latter, may be maintained by cardiac fibroblasts through cytokines and chemokines. The C-terminal repetitive domain of Clostridium difficile toxin A (ARU) is homologous to GTF and exhibites adjuvant activity in mucosal immunity. In second part of this study, we demonstrate that ARU is sufficient to induce IL-6, IL-8 and MCP-1 production in endothelial cells through serum- and calcium-dependent manner. Inhibition results demonstrate that cytokine production in ARU-activated HUVEC is through PI3K、PKC、PTK、MAPKs and NF-kB activation. Both IL-8 and MCP-1 trigger leukocytes chemotaxis in vitro. These results suggest that mucosal adjuvant activity of C-terminus of TcdA may also attribute to the interaction of endothelial cells to release IL-6, which is important for maturating plasma cells. Take together; we hypothesized that the C-terminal repeates of GTFs, similar to ARU, might be involved in the binding of endothelial cells.
|
|---|
