Cisplatin increases TNF-α mRNA stability in kidney proximal tubule cells

Abstract

Cisplatin induces acute renal injury in part by increasing the production of TNF-α. However, the mechanism by which cisplatin increases renal TNF-α expression is not known. The transcription, translation, and stability of TNF-α mRNA are sites of regulation of TNF-α production. This study investigated the effects of cisplatin on TNF-α mRNA stability and the role of MAP kinases in this process in cultured renal proximal tubule cells. Cisplatin increased the expression of TNF-α 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-α expression significantly. Cisplatin also increased the stability of TNF-α 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-α 3′UTR. These results are consistent with the view that cisplatin increases TNF-α mRNA stability in a MAP kinase-independent manner. The stabilization of TNF-α mRNA by cisplatin may involve the binding of certain proteins to AU-rich regions in the 3′UTR. Copyright © Informa Healthcare.