IL-33 exacerbates acute kidney injury.

Abstract

Inflammation contributes to the pathogenesis of acute kidney injury (AKI). IL-33 is a proinflammatory cytokine, but its role in AKI is unknown. Here we observed increased protein expression of full-length IL-33 in the kidney following induction of AKI with cisplatin. To determine whether IL-33 promotes injury, we administered soluble ST2 (sST2), a fusion protein that neutralizes IL-33 activity by acting as a decoy receptor. Compared with cisplatin-induced AKI in untreated mice, mice treated with sST2 had fewer CD4 T cells infiltrate the kidney, lower serum creatinine, and reduced acute tubular necrosis (ATN) and apoptosis. In contrast, administration of recombinant IL-33 (rIL-33) exacerbated cisplatin-induced AKI, measured by an increase in CD4 T cell infiltration, serum creatinine, ATN, and apoptosis; this did not occur in CD4-deficient mice, suggesting that CD4 T cells mediate the injurious effect of IL-33. Wildtype mice that received cisplatin and rIL-33 also had higher levels of the proinflammatory chemokine CXCL1, which CD T cells produce, in the kidney compared with CD4-deficient mice. Mice deficient in the CXCL1 receptor also had lower serum creatinine, ATN, and apoptosis than wildtype mice following cisplatin-induced AKI. Taken together, IL-33 promotes AKI through CD4 T cell-mediated production of CXCL1. These data suggest that inhibiting IL-33 or CXCL1 may have therapeutic potential in AKI.

• Authors: Ali Akcay, Quocan Nguyen, Zhibin He, Kultigin Turkmen, Dong Won Lee, Ana Andres Hernando, Christopher Altmann, Aysun Toker, Arijana Pacic, Danica Galesic Ljubanovic, Alkesh Jani, Sarah Faubel, Charles L Edelstein
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 22 Issue 11 Pg. 2057-67 (Nov 2011) ISSN: 1533-3450 [Electronic] United States
• PMID: 21949094 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Chemokine CXCL1
• Cxcl1 protein, mouse
• Il33 protein, mouse
• Interleukin-33
• Interleukins
• Cisplatin

Topics

• Acute Kidney Injury (chemically induced, immunology, pathology)
• Animals
• Antineoplastic Agents (toxicity)
• CD4-Positive T-Lymphocytes (cytology, immunology)
• Chemokine CXCL1 (immunology, metabolism)
• Cisplatin (toxicity)
• Disease Models, Animal
• Endothelial Cells (immunology, metabolism, pathology)
• Flow Cytometry
• Interleukin-33
• Interleukins (blood, immunology, pharmacology)
• Kidney Glomerulus (immunology, metabolism, pathology)
• Kidney Tubular Necrosis, Acute (chemically induced, immunology, pathology)
• Male
• Mice
• Mice, Inbred C57BL