Chlamydophila pneumoniae induces p44/p42 mitogen-activated protein kinase activation in human fibroblasts through Toll-like receptor 4.
Chlamydophila pneumoniae, an obligately intracellular Gram-negative bacterium and a common causative agent of respiratory tract infections, has been implicated in the induction and progression of atherosclerosis and coronary artery disease. In this study, the signalling mechanism of C. pneumoniae in human fibroblasts, a prominent cell population in chronic inflammation and persistent infection, contributing to plaque formation, was investigated. C. pneumoniae elementary bodies were demonstrated to up-regulate the phosphorylation of p44/p42 mitogen-activated protein kinase (MAPK) in human fibroblasts. The effect was independent of the chlamydial lipopolysaccharide and was likely to be mediated by a heat-labile chlamydial protein. Furthermore, an anti-Toll-like receptor 4 (TLR4) antibody was shown to abolish C. pneumoniae-induced cell activation, whereas an anti-TLR2 antibody had no effect, indicating the role of TLR4 in p44/p42 MAPK activation. Ca2+/calmodulin-dependent protein kinase inhibitor KN-62 and phosphodiesterase 4 (PDE 4) inhibitor Rolipram enhanced C. pneumoniae-induced MAPK phosphorylation and attenuated C. pneumoniae infectivity in vitro. Together the results indicate that C. pneumoniae triggers rapid TLR4-mediated p44/p42 MAPK activation in human fibroblasts and chemical enhancement of MAPK phosphorylation modulates in vitro infection at the molecular level.
Haralambieva
Iana H
IH
Departments of Microbiology1 and Chemistry and Biochemistry2, Medical University, Zdrave 2 str., 1431 Sofia, Bulgaria.
Iankov
Ianko D
ID
Departments of Microbiology1 and Chemistry and Biochemistry2, Medical University, Zdrave 2 str., 1431 Sofia, Bulgaria.
Ivanova
Petya V
PV
Departments of Microbiology1 and Chemistry and Biochemistry2, Medical University, Zdrave 2 str., 1431 Sofia, Bulgaria.
Mitev
Vanio
V
Departments of Microbiology1 and Chemistry and Biochemistry2, Medical University, Zdrave 2 str., 1431 Sofia, Bulgaria.
Mitov
Ivan G
IG
Departments of Microbiology1 and Chemistry and Biochemistry2, Medical University, Zdrave 2 str., 1431 Sofia, Bulgaria.
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000907:Antibodies, Bacterial / Q000502:physiology; D001426:Bacterial Proteins / Q000276:immunology; D002478:Cells, Cultured; D016993:Chlamydophila pneumoniae / Q000187:drug effects / Q000502:physiology*; D004789:Enzyme Activation / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000201:enzymology* / Q000382:microbiology; D006801:Humans; D008562:Membrane Glycoproteins / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000502:physiology*; D020889:Rolipram / Q000494:pharmacology; D015398:Signal Transduction / Q000276:immunology; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D015854:Up-Regulation
D000907:Antibodies, Bacterial; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; C063302:KN 62; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020889:Rolipram