Endotoxin and cisplatin synergistically stimulate TNF-α production by renal epithelial cells

Abstract

Acute renal failure often occurs in the clinical setting of multiple renal insults. Tumor necrosis factor-␣ (TNF-␣) has been implicated in the pathogenesis of cisplatin nephrotoxicity, ischemia-reperfusion injury, and endotoxininduced acute renal failure. The current studies examined the interactions between cisplatin and endotoxin with particular emphasis on TNF-␣ production. Treatment of cultured murine proximal tubule cells (TKPTS cells) with cisplatin resulted in a modest production of TNF-␣, while treatment with endotoxin did not result in any TNF-␣ production. However, the combination of cisplatin and endotoxin resulted in large amounts of TNF-␣ synthesis and secretion. The stimulation of TNF-␣ production was dependent on 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 cisplatinϩendotoxin-stimulated TNF-␣ 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-␣ 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-␣ mRNA in a p38 MAPK-dependent manner. These interactions between cisplatin and endotoxin may be relevant to the pathogenesis of cisplatin nephrotoxicity in humans. p38 MAPK; Mnk1; eIF4E; acute renal failure; LPS ACUTE RENAL FAILURE CAN DEVELOP in a variety of clinical situations such as ischemia, sepsis, and administration of nephrotoxic agents. Studies using experimental models of acute renal failure have identified a large number of putative pathophysiological mediators (42, 45). The majority of these studies have employed models of acute renal injury subsequent to a single renal insult (25). However, acute renal failure in humans often occurs in complex clinical settings in which patients may be exposed to a number of different renal insults (45). It has been suggested that the failure in humans of therapeutic interventions based on single-insult animal studies may be due, in part, to the multiplicity of renal insults in human acute renal failure (13,25).Sepsis is a common cause of acute renal failure, accounting for up to 60% of cases in some series (3, 41). The prognosis for sepsis-associated acute renal failure is particularly grim, with reported mortality rates as high as 95% (3,20). TNF-␣ is an important mediator of the systemic and renal effects of sepsis. The production of TNF-␣ in sepsis results from the activation of TLR receptors by bacterial products such as endotoxin (1, 7). Neutralization of TNF-␣ using a soluble receptor protected against ...

TLR4 Signaling Mediates Inflammation and Tissue Injury in Nephrotoxicity

“…7 Moreover, p38 MAPK activation contributes to TNF-␣ production and renal failure in response to cisplatin. 4,47 The partial reduction in renal p38 MAPK activity in the Tlr4-deficient mice is consistent with a role for TLR4 in cisplatininduced p38 MAPK activation.…”

A Role for Tubular Necroptosis in Cisplatin-Induced AKI

“…27 Therefore, the severe inflammatory responses in WT mice could result predominantly from tubular cell necroptosis, although cisplatin treatment alone can induce proinflammatory cytokine expression. 22 Furthermore, the inflammatory cytokines induced at day 2 to day 4 after cisplatin treatment could function in combination to stimulate increased necroptosis. Previous studies have shown that poly (ADP-ribose)-polymerase 1, Bax, p53, and cyclophilin D are involved in cisplatin-induced AKI, 4,5,7,9 but the relationship between these pathways and necroptosis in AKI is unclear.…”

“…It is apparent that the increase of RIP1 and RIP3 protein levels during cisplatin-induced AKI contributes to the necroptosis Blockade of Necroptotic Pathway Impairs the Induction of Some Proinflammatory Cytokines in Cisplatin-Induced AKI Model Inflammation in lesions has been shown to play an important role in the acceleration of cisplatin nephrotoxicity. 3,21 Cisplatin has been reported to induce cytokine production in renal tubular cells directly, 22 and necrotic death may also exacerbate inflammation. Therefore, we investigated whether blocking necroptosis by RIP3 deficiency affects cisplatin-induced inflammatory cytokine expression in proximal tubules in vivo.…”

“…Both Cisplatin-and Cytokine-Induced PTC Necroptosis Contribute to Cisplatin-Induced AKI Because cisplatin treatment induces not only PTC necroptosis but also proinflammatory cytokine secretion, 22 cisplatin-induced necroptosis might be caused by autocrine of the cisplatin-induced cytokines. 23 Co-stimulation of renal tubular cells with a combination of TNF-a, TWEAK, and IFN-g (referred as TTI) is known to result in caspase-independent cell death or necroptosis.…”

A Possible Mechanism of Cisplatin-Induced Tumor Necrosis Factor (TNF)-α Production in Murine Macrophages

“…On the other hand, the activation of p38 MAPK and JNK generally results in inflammation [8,9,11]. Ramesh et al reported that cisplatin induced TNF-α mRNA expression via activation of the p38 MAPK pathway in renal proximal tubular cells [12]. However, the possible mechanism of cisplatin-induced TNF-α expression in macrophages has not been fully elucidated.…”