Cisplatin Increases TNF-α 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.