title: Cisplatin primes murine peritoneal macrophages for enhanced expression of nitric oxide, proinflammatory cytokines, TLRs, transcription factors and activation of MAP kinases upon co-incubation with L929 cells.
abstract: Cisplatin, a chemotherapeutic drug, may also act as a biological response modifier. Cisplatin (10mug/ml) treatment of macrophages for 24h activates them to produce enhanced amounts of nitric oxide (NO), ROI, proinflammatory cytokines and exhibit increased tumoricidal activity, which may or may not be contact mediated. In the present investigation, we report that the treatment of macrophages with cisplatin for a short period of 2h is sufficient to make them more receptive to interaction with tumor cells. Macrophages pretreated with cisplatin for 2h, and co-incubated with L929 cells, produced enhanced NO, TNF-alpha, IL-1beta, IL-12 and IFN-gamma. Production of NO, TNF-alpha, IL-1beta, IL-12 and IFN-gamma was maximum at 24h of co-incubation. Enhanced transcription of iNOS, TNF-alpha, IL-1beta, IL-12 and IFN-gamma genes in cisplatin-pretreated macrophages were observed between 12 and 24h of co-incubation with L929 cells. Cisplatin-treated macrophages on co-incubation with L929 cells also expressed enhanced transcription of Toll-like receptor (TLR)-2 and TLR-4 genes and their proteins. It is observed that cisplatin-pretreated macrophages on co-incubation with L929 cells showed activation of mitogen-activated protein (MAP) kinases and NF-kappaB. Pharmacological inhibitors like PD98059, SB202190 and wortmannin strongly inhibited the production of NO and proinflammatory cytokines suggesting the probable role of p42/44, p38 MAPK and PI3K in the above process. The c-Jun amino terminal kinase (JNK) inhibitor SP600125 was less effective in inhibiting the production of NO and proinflammatory cytokines. The data thus suggests that pretreatment of macrophages with cisplatin makes them biologically more responsive to interaction with L929 cells and become activated.
authors.affiliation: School of Biotechnology, Banaras Hindu University, Varanasi 221005, India.
authors.forename: Puja
authors.initials: P
authors.lastname: Chauhan
authors.forename: Ajit
authors.initials: A
authors.lastname: Sodhi
authors.forename: Anju
authors.initials: A
authors.lastname: Shrivastava
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D002461:Cell Line, Transformed; D002945:Cisplatin / Q000494:pharmacology*; D018920:Coculture Techniques; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic; D005419:Flavonoids / Q000494:pharmacology; D018836:Inflammation Mediators / Q000276:immunology; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors; D020935:MAP Kinase Signaling System / Q000276:immunology; D008262:Macrophage Activation / Q000187:drug effects*; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D000873:Anthracenes; D016207:Cytokines; D005419:Flavonoids; D018836:Inflammation Mediators; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C432165:pyrazolanthrone; D009569:Nitric Oxide; D048670:MAP Kinase Kinase 4; D002945:Cisplatin; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D000077191:Wortmannin