Th1 and Th2 Related Cytokines Influence Systemic Inflammatory Responses in Renal Injuries Induced by Ischemia and Reperfusion

Vanessa Nunes de Paiva^1*, Rafael Assumpção Larocca², Rebecca Monteiro, M. M.², Patrícia Semedo³, Marlene dos Reis, A.⁴, Alvaro Pacheco-Silva³ & Niels Câmara, O. S.^2,3

¹Institute of Reconstructive Neurobiology, University of Bonn, Life & Brain Centre, Bonn, Germany
²Laboratory of Transplantation Immunobiology, Department of Immunology, University of São Paulo, São Paulo, Brazil
³Laboratory of Clinical and Experimental Immunology, Nephrology Division, Department of Medicine, Federal University of São Paulo UNIFESP-EPM, São Paulo, Brazil
⁴Department of Pathology, Federal university of Uberaba, Minas Gerais, Brazil

Dr. Vanessa Nunes de Paiva, Institute of Reconstructive Neurobiology, University of Bonn, Life & Brain Centre, Bonn, Germany.

Keywords: Acute Renal Failure; Ischemia and Reperfusion Injury; Cytokines; IL-10; IL-12

Abstract

Renal ischemia/reperfusion injury (IRI) is the major cause of acute kidney injury (AKI) in native and transplanted kidneys, with a complex pathogenesis involving leukocyte infiltration, and release of proinflammatory mediators by tubular cells. Recent evidences have shown a critical role of the CD4⁺ T cells, and the balance between Th1/Th2 cells as possible effector mechanism. In order to evaluate the role of Th1/Th2 immune response in this system, IL-4, IL-10, IL-12 deficient mice and IL-12/IL-10 double deficient mice were used. Moreover, for adoptive transference studies we generated chimeric mice on C57BL/6 background. Data was collected 24 hours post IRI. Renal function was evaluated by serum urea measurement and renal morphometric histology analyses. Gene expression of IL-6, MCP-1 and HO-1 were also investigated. Strikingly, IL-4, IL-10 and IL-12/IL-10 KO deficient animals presented higher renal dysfunction when compared to controls, followed by higher expression of HO-1, IL-6 and MCP-1. Conversely, IL-12 KO and (IL-12 KO > WT) chimeric mice were absolutely protected from IRI. We also observed in the (IL-12 KO > WT) chimeric mice a reduction in urea levels, a better renal outcome and down-regulation in IL-6 expression when compared with WT > WT chimeras, suggesting an indirect role of Th1 response. Moreover, IL-6 was not detected in the serum of IL-12 deficient mice while neutrophil-recruiting chemokine KC was elevated in IL-4, IL-10 and IL-2/IL-10 deficient mice. Yet, IL-4 was absent in IL-10 and IL-12/IL-10 deficient mice serum. Thus our results confirm that Th1/Th2 related cytokines are critically involved during renal IRI.

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