title: Endogenous IL-10 attenuates cisplatin nephrotoxicity: role of dendritic cells.
abstract: Sterile inflammation is associated with tissue injury and organ failure. Recent studies indicate that certain endogenous cytokines and immune cells may limit tissue injury by reducing immune-mediated inflammatory responses. Cisplatin is a commonly used anticancer chemotherapeutic agent but causes acute kidney injury and dysfunction. In a recent study, we showed that renal dendritic cells attenuate cisplatin-induced kidney injury by reducing inflammation. In this study, we investigated the effect of endogenous IL-10 and dendritic cell IL-10 in cisplatin-mediated kidney injury. Cisplatin treatment caused increases in renal IL-10R1 expression and STAT3 phosphorylation. In response to cisplatin treatment, IL-10 knockout mice showed more rapid and greater increases in blood urea nitrogen and serum creatinine compared with wild-type mice, indicating that endogenous IL-10 ameliorates kidney injury in cisplatin nephrotoxicity. Renal infiltration of IFN-γ-producing neutrophils was markedly increased in IL-10 knockout mice compared with wild-type mice. However, IFN-γ neutralization had no impact on renal dysfunction, suggesting IFN-γ-independent mechanisms of tissue injury in cisplatin nephrotoxicity. Renal dendritic cells showed high expression of IL-10 in response to cisplatin treatment. We further investigated the effect of dendritic cell-derived IL-10 in cisplatin nephrotoxicity using a conditional cell ablation approach. Mixed bone marrow chimeric mice lacking IL-10 in dendritic cells showed moderately greater renal dysfunction than chimeric mice positive for IL-10 in dendritic cells. These data demonstrate that endogenous IL-10 reduces cisplatin nephrotoxicity and associated inflammation. Moreover, IL-10 produced by dendritic cells themselves accounts for a portion of the protective effect of dendritic cells in cisplatin nephrotoxicity.
authors.affiliation: Division of Nephrology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
authors.forename: Raghu Kempegowda
authors.initials: RK
authors.lastname: Tadagavadi
authors.forename: William Brian
authors.initials: WB
authors.lastname: Reeves
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D002469:Cell Separation; D002945:Cisplatin / Q000009:adverse effects*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D005434:Flow Cytometry; D007150:Immunohistochemistry; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000276:immunology; D007674:Kidney Diseases / Q000139:chemically induced / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000970:Antineoplastic Agents; D016753:Interleukin-10; D002945:Cisplatin