title: Interleukin-6 deficiency accelerates cisplatin-induced acute renal failure but not systemic injury.
abstract: 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.
authors.affiliation: Laboratory of Forensic Toxicology, Faculty of Pharmacy, Takasaki University of Health and Welfare, 60 Nakaorui-machi, Takasaki 370-0033, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Mitazaki
authors.forename: N
authors.initials: N
authors.lastname: Kato
authors.forename: M
authors.initials: M
authors.lastname: Suto
authors.forename: K
authors.initials: K
authors.lastname: Hiraiwa
authors.forename: S
authors.initials: S
authors.lastname: Abe
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001806:Blood Urea Nitrogen; D002945:Cisplatin / Q000633:toxicity*; D020869:Gene Expression Profiling; D051547:Heme Oxygenase-1 / Q000378:metabolism; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000097:blood / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis / Q000235:genetics; D016019:Survival Analysis; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis / Q000235:genetics; D051020:bcl-X Protein / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D015850:Interleukin-6; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D051547:Heme Oxygenase-1; D002945:Cisplatin