Interleukin-6 Deficiency Accelerates Cisplatin-induced Acute Renal Failure but Not Systemic Injury

Cisplatin (CDDP), a major chemotherapeutic agent used to treat solid tumors, is known to induce acute renal failure (ARF). The progression of tissue injury involves the coordination of inflammatory and repair responses. Interleukin-6 (IL-6) has been suggested to modulate inflammatory and repair processes in various tissue injuries. In this study, we analyzed IL-6 regulation during CDDP-induced ARF in wild-type (WT) mice and determined the pathological role of IL-6 using IL-6 knockout ((-/-)) mice. A correlation between increase in serum IL-6 level and blood urea nitrogen level was found in WT mice. Renal IL-6 expression in most proximal tubular cells and suppressor of cytokine signaling 3 (SOCS3) gene expression significantly increased in WT mice after administration of CDDP, suggesting active IL-6 signaling during CDDP-induced ARF development. Interestingly, renal dysfunction occurred soon after administration of CDDP and became more severe in IL-6(-/-) mice than that in WT mice. In contrast, the survival rate of IL-6(-/-) mice (50% at 8 days) was better than that of WT mice (10%). Induction levels of proapoptotic Bcl-2 associated X protein (Bax) in renal proximal tubular cells was significantly higher in IL-6(-/-) mice than in WT mice at 24h after CDDP injection. Levels of antiapoptotic proteins, Bcl-2 and Bcl-extra large (Bcl-x(L)), in IL-6(-/-) groups were significantly higher than those in CDDP-treated WT groups throughout the experimental period. Bax might contribute to the development of CDDP-induced ARF at 24h; however, high expression levels of Bcl-x(L) and Bcl-2 might overcome the proapoptosis signaling at 72 h in IL-6(-/-) mice. These results indicated that local and systemic elevation of IL-6 contributes to the development of CDDP-induced ARF and that IL-6 produced in renal tubular cells prevents progression of ARF at the early stage. IL-6 deficiency accelerates CDDP-induced ARF but not development of systemic injury.