Endogenous IL-10 attenuates cisplatin nephrotoxicity: role of dendritic cells.
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.
Tadagavadi
Raghu Kempegowda
RK
Division of Nephrology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
Reeves
William Brian
WB
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
D000970:Antineoplastic Agents; D016753:Interleukin-10; D002945:Cisplatin