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Am J Physiol Renal Physiol (October 10, 2006). doi:10.1152/ajprenal.00277.2006
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Submitted on July 19, 2006
Accepted on October 5, 2006

Endotoxin and cisplatin synergistically stimulate TNF-{alpha} production by renal epithelial cells

Ganesan Ramesh1, Scot R. Kimball2, Leonard S. Jefferson3, and William Brian Reeves4*

1 Department of Medicine, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States
2 Department of Cellular and Molecular Physiology, Pennsylvania State College of Medicine, Hershey, Pennsylvania, United States
3 Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey,, Pennsylvania, United States
4 Department of Medicine, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States; Department of Medicine, Lebanon VA Medical Center, Lebanon, Pennsylvania, United States

* To whom correspondence should be addressed. E-mail: wreeves{at}psu.edu.

Acute renal failure often occurs in the clinical setting of multiple renal insults. Tumor necrosis factor-{alpha} (TNF-{alpha}) has been implicated in the pathogenesis of cisplatin nephrotoxicity, ischemia-reperfusion injury and endotoxin-induced acute renal failure. The current studies examined the interactions between cisplatin and endotoxin with particular emphasis on TNF-{alpha} production. Treatment of cultured murine proximal tubule cells (TKPTS cells) with cisplatin resulted in a modest production of TNF-{alpha} while treatment with endotoxin did not result in any TNF-{alpha} production. However, the combination of cisplatin and endotoxin resulted in large amounts of TNF-{alpha} synthesis and secretion. The stimulation of TNF-{alpha} production was dependent upon cisplatin-induced activation of p38 MAPK and was associated with phosphorylation of the translation initiation factor eIF4E and its upstream kinase Mnk1. Inhibition of p38 MAPK and, to a lesser extent, ERK, reduced cisplatin+endotoxin stimulated TNF-{alpha} production and phosphorylation of Mnk1 and eIF4E. Synergy between cisplatin and endotoxin was also observed in certain tumor cell lines, but not in macrophages. In macrophages, in contrast to TKPTS cells, endotoxin alone activated p38 MAPK and stimulated TNF-{alpha} production with no added impact by cisplatin. The combination of cisplatin and endotoxin did not result in synergistic production of other cytokines, e.g. MCP-1 and MIP2, by TKPTS cells. In summary, these studies indicate that cisplatin sensitizes renal epithelial cells to endotoxin and dramatically increases the translation of TNF-{alpha} mRNA in a p38 MAPK dependent manner. These interactions between cisplatin and endotoxin may be relevant to the pathogenesis of cisplatin nephrotoxicity in humans.




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