Protein kinase Cdelta and protein tyrosine kinase regulate peptidoglycan-induced nuclear factor-kappaB activation and inducible nitric oxide synthase expression in mouse peritoneal macrophages in vitro.
Bacteria and their ubiquitous cell wall component peptidoglycan (PGN) activate the innate immune system of the host and induce the release of inflammatory molecules. Nitric oxide (NO) is a potent molecule involved in the cytotoxic effects mediated by macrophages (MPhi) against microorganisms. This study investigates the signaling pathway involved in inducible nitric oxide synthase (iNOS) expression and nitric oxide release caused by peptidoglycan from Staphylococcus aureus in mouse peritoneal macrophages. Protein tyrosine kinase inhibitor, genestein and PKCdelta inhibitor, rottlerin attenuated the PGN-induced expression of iNOS and NO. H-7, a PKC inhibitor did not significantly affected the PGN-induced iNOS expression and NO release. NF-kappaB inhibitor, curcumin also inhibited PGN-induced NO release. Treatment of MPhi with PGN caused an increase in protein tyrosine kinase activity, expression and activation of PKCdelta, IkappaB phosphorylation and p65 (NF-kappaB) nuclear translocation. The PGN-induced IkappaB phosphorylation and p65 nuclear translocation was inhibited in macrophages pretreated with rottlerin and genestein. No paracrine or autocrine effect of TNF-alpha on PGN-induced iNOS expression and NO release was observed. These observations suggest that PGN induces enhanced expression of iNOS and NO production through activation of protein tyrosine kinases and PKCdelta, which in turn initiates NF-kappaB activation and translocation to nucleus.
Bhatt
Kunal H
KH
School of Biotechnology, Faculty of Science, Banaras Hindu University, Varanasi 221005, India.
Pandey
Rajeev Kumar
RK
Dahiya
Yogesh
Y
Sodhi
Ajit
A
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D019833:Genistein / Q000494:pharmacology; D020672:I-kappa B Proteins / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D010457:Peptidoglycan / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects; D051745:Protein Kinase C-delta / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019323:omega-N-Methylarginine / Q000494:pharmacology
D000098:Acetophenones; D001578:Benzopyrans; D020672:I-kappa B Proteins; D016328:NF-kappa B; D010457:Peptidoglycan; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019833:Genistein; C085746:rottlerin; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D011505:Protein-Tyrosine Kinases; D051745:Protein Kinase C-delta