Mechanism of NF-kappa B translocation in macrophages treated in vitro with cisplatin.
In murine peritoneal macrophages cisplatin (cis-dichlorodiammine platinum (II)), a potent chemoimmunotherapeutic drug modulates the expression of several cytokines which contain nuclear factor kappa B (NF-kappaB) binding site suggesting the involvement of NF-kappaB in the activation process of macrophages by cisplatin. Therefore, we analyzed the effect of cisplatin treatment on NF-kappaB expression and activation in macrophages. The underlying mechanism of NF-kappaB translocation was also investigated. Cisplatin treatment increased cellular NF-kappaB content in macrophages treated for 60 min. NF-kappaB translocation was biphasic. Cisplatin-induced translocation of NF-kappaB took place within 5 min and reached its optimum by 15 min. A second phase of nuclear transfer of NF-kappaB was observed at 3 h of cisplatin treatment which was dependent on H2O2 production in cisplatin-treated macrophages. It was observed that cisplatin-induced NF-kappaB translocation involves serine/threonine phosphatases 1/2A, protein tyrosine phosphatases and genestein sensitive protein tyrosine kinase activities. H-7 sensitive protein kinase C do not fall in the signaling pathway of cisplatin leading to the translocation of NF-kappaB. Both cytosolic and membrane-associated factors were required for the induction of NF-kappaB translocation by cisplatin in macrophages.
School of Biotechnology, Banaras Hindu University, Varanasi, India. ajitsodhi@hotmail.com
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D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002147:Calmodulin / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology; D002478:Cells, Cultured; D002945:Cisplatin / Q000494:pharmacology*; D005260:Female; D006861:Hydrogen Peroxide / Q000378:metabolism; D017737:Macrophages, Peritoneal; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism
D002147:Calmodulin; D016328:NF-kappa B; D006861:Hydrogen Peroxide; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C095895:calcium-calmodulin-activated histone 3 arginine kinase; D010744:Phosphoric Monoester Hydrolases; D002945:Cisplatin; D002118:Calcium