Cisplatin increases TNF-alpha mRNA stability in kidney proximal tubule cells.
Cisplatin induces acute renal injury in part by increasing the production of TNF-alpha. However, the mechanism by which cisplatin increases renal TNF-alpha expression is not known. The transcription, translation, and stability of TNF-alpha mRNA are sites of regulation of TNF-alpha production. This study investigated the effects of cisplatin on TNF-alpha mRNA stability and the role of MAP kinases in this process in cultured renal proximal tubule cells. Cisplatin increased the expression of TNF-alpha mRNA by proximal tubule cells in a time- and dose-dependent manner, as well as activated p42/44 ERK kinase, p38 MAP kinase, and JNK in a dose-dependent manner. The inhibition of these pathways reduced TNF-alpha expression significantly. Cisplatin also increased the stability of TNF-alpha mRNA, but this effect was not mediated by MAP kinases and did not require the synthesis of a new protein. The treatment of cells with cisplatin induced the formation of complexes of cytosolic proteins and the AU-rich region of the TNF-alpha 3'UTR. These results are consistent with the view that cisplatin increases TNF-alpha mRNA stability in a MAP kinase-independent manner. The stabilization of TNF-alpha mRNA by cisplatin may involve the binding of certain proteins to AU-rich regions in the 3'UTR.
Ramesh
Ganesan
G
The Penn State College of Medicine, Division of Nephrology, Hershey, Pennsylvania 17033, USA.
Brian Reeves
W
W
D058186:Acute Kidney Injury / Q000139:chemically induced; D000818:Animals; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D002945:Cisplatin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000187:drug effects*; D007687:Kidney Tubules, Proximal / Q000166:cytology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D016133:Polymerase Chain Reaction; D020871:RNA Stability / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D020928:Mitogen-Activated Protein Kinases; D002945:Cisplatin