KN-62 enhances Chlamydia pneumoniae-induced p44/p42 mitogen-activated protein kinase activation in murine fibroblasts and attenuates in vitro infection.
Chlamydia pneumoniae elementary bodies were demonstrated to increase the proliferation of murine fibroblast cell line L-929 and rapidly activate p44/p42 mitogen-activated protein kinase (MAPK) in a protein kinase C (PKC) and protein kinase A (PKA)-independent way. Ca(2+)/calmodulin-dependent protein kinase (CaM kinase) inhibitor KN-62 significantly enhanced C. pneumoniae-induced MAPK phosphorylation, suggesting negative control of CaM kinase pathway on the MAPK cascade. In in vitro infection assay, the upstream MAPK kinase 1/2 inhibitor U0126 increased 2.5-fold C. pneumoniae infectivity in L-929 cells, while KN-62 reduced the infection by 36%. Our findings provide insight into the molecular mechanisms of bacterium-host cell interactions and demonstrate the protective role of MAPK in murine fibroblasts, suggesting novel therapeutic approaches to the treatment and prevention of chlamydial infections.
Haralambieva
Iana
I
Department of Microbiology, Preclinical University Center, Medical University, Zdrave 2 Street, 1431, Sofia, Bulgaria. iana@medfac.acad.bg
Iankov
Ianko
I
Mitev
Vanio
V
Mitov
Ivan
I
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D000942:Antigens, Bacterial / Q000378:metabolism; D002070:Butadienes / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002455:Cell Division; D002460:Cell Line; D023521:Chlamydophila Infections / Q000188:drug therapy / Q000378:metabolism*; D016993:Chlamydophila pneumoniae / Q000201:enzymology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005347:Fibroblasts / Q000166:cytology / Q000382:microbiology; D066298:In Vitro Techniques; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D020239:Receptor Cross-Talk / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
D000942:Antigens, Bacterial; D002070:Butadienes; D004791:Enzyme Inhibitors; D009570:Nitriles; C113580:U 0126; C063302:KN 62; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases