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      IL-10 Deficiency Increases Renal Ischemia-Reperfusion Injury

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          Background: Renal ischemia-reperfusion (IR) injury is a frequent cause of acute kidney injury, which results in high morbidity and mortality. Inflammation is an important factor that is involved in kidney repair after renal IR injury. IL-10 is a potent anti-inflammatory cytokine that inhibits inflammatory pathways, but the role of IL-10 in repairing renal IR injury is not known. Here, we investigated the role of IL-10 in kidney repair after renal IR injury. Methods: We used an IL-10<sup>-/-</sup> mouse model and examined the serologic and histomorphology of kidney after IR injury. We also measured ki67, TNF-α, IL-6, and macrophages with immunohistochemistry or Western blotting. Results: There was a greater increase in serum creatinine in IL-10<sup>-/-</sup> mice than in wild-type (WT) mice. And compared with WT mice, IL-10<sup>-/-</sup> mice had increased histologic renal injury and decreased proliferation. Moreover, the expression of TNF-α, IL-6 and macrophages was clearly increased in IL-10<sup>-/-</sup> mice compared with the WT mice. Conclusion: These data reveal an important role for IL-10 in the improvement of renal IR injury, acting through suppression of inflammatory mediators, and that IL-10 would be a crucial target for the treatment of IR injury.

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          Most cited references 22

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          Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes

           B Bennett,  R Malefyt,  la De (1991)
          In the present study we demonstrate that human monocytes activated by lipopolysaccharides (LPS) were able to produce high levels of interleukin 10 (IL-10), previously designated cytokine synthesis inhibitory factor (CSIF), in a dose dependent fashion. IL-10 was detectable 7 h after activation of the monocytes and maximal levels of IL-10 production were observed after 24-48 h. These kinetics indicated that the production of IL-10 by human monocytes was relatively late as compared to the production of IL-1 alpha, IL-1 beta, IL-6, IL-8, tumor necrosis factor alpha (TNF alpha), and granulocyte colony-stimulating factor (G-CSF), which were all secreted at high levels 4-8 h after activation. The production of IL-10 by LPS activated monocytes was, similar to that of IL-1 alpha, IL-1 beta, IL-6, IL-8, TNF alpha, granulocyte-macrophage colony-stimulating factor (GM-CSF), and G-CSF, inhibited by IL-4. Furthermore we demonstrate here that IL-10, added to monocytes, activated by interferon gamma (IFN-gamma), LPS, or combinations of LPS and IFN-gamma at the onset of the cultures, strongly inhibited the production of IL-1 alpha, IL-1 beta, IL-6, IL-8, TNF alpha, GM-CSF, and G-CSF at the transcriptional level. Viral-IL-10, which has similar biological activities on human cells, also inhibited the production of TNF alpha and GM-CSF by monocytes following LPS activation. Activation of monocytes by LPS in the presence of neutralizing anti-IL-10 monoclonal antibodies resulted in the production of higher amounts of cytokines relative to LPS treatment alone, indicating that endogenously produced IL-10 inhibited the production of IL-1 alpha, IL-1 beta, IL-6, IL-8, TNF alpha, GM-CSF, and G-CSF. In addition, IL-10 had autoregulatory effects since it strongly inhibited IL-10 mRNA synthesis in LPS activated monocytes. Furthermore, endogenously produced IL-10 was found to be responsible for the reduction in class II major histocompatibility complex (MHC) expression following activation of monocytes with LPS. Taken together our results indicate that IL-10 has important regulatory effects on immunological and inflammatory responses because of its capacity to downregulate class II MHC expression and to inhibit the production of proinflammatory cytokines by monocytes.
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            Ischemic acute renal failure: an inflammatory disease?

            Inflammation plays a major role in the pathophysiology of acute renal failure resulting from ischemia. In this review, we discuss the contribution of endothelial and epithelial cells and leukocytes to this inflammatory response. The roles of cytokines/chemokines in the injury and recovery phase are reviewed. The ability of the mouse kidney to be protected by prior exposure to ischemia or urinary tract obstruction is discussed as a potential model to emulate as we search for pharmacologic agents that will serve to protect the kidney against injury. Understanding the inflammatory response prevalent in ischemic kidney injury will facilitate identification of molecular targets for therapeutic intervention.
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              Regulatory T cells suppress innate immunity in kidney ischemia-reperfusion injury.

              Both innate and adaptive mechanisms participate in the pathogenesis of kidney ischemia-reperfusion injury (IRI), but the role of regulatory immune mechanisms is unknown. We hypothesized that the anti-inflammatory effects of CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) protect against renal IRI. Partial depletion of Tregs with an anti-CD25 mAb potentiated kidney damage induced by IRI. Reducing the number of Tregs resulted in more neutrophils, macrophages, and innate cytokine transcription in the kidney after IRI but did not affect CD4(+) T cells or B cells. We performed adoptive transfer of lymph node cells from wild-type mice or FoxP3-deficient Scurfy mice into T cell- and B cell-deficient RAG-1 knockout mice to generate mice with and without FoxP3(+) Tregs, respectively. FoxP3(+) Treg-deficient mice accumulated a greater number of inflammatory leukocytes after renal IRI than mice containing Tregs. To confirm that a lack of Tregs potentiated renal injury, we co-transferred isolated Tregs and Scurfy lymph node cells; Treg repletion significantly attenuated IRI-induced renal injury and leukocyte accumulation. Furthermore, although adoptive transfer of wild-type Tregs into RAG-1 knockout mice was sufficient to prevent kidney IRI, transfer of IL-10-deficient Tregs was not. Taken together, these results demonstrate that Tregs modulate injury after kidney IRI through IL-10-mediated suppression of the innate immune system.

                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                December 2014
                31 October 2014
                : 128
                : 1-2
                : 37-45
                aDivision of Nephrology, Department of Medicine, bDivision of Cardiovascular Surgery, Department of Surgery, and cGeneral Clinical Research Center, Nanjing Medical University, Nanjing First Hospital, Nanjing, China
                Author notes
                *Chang-Chun Cao, MD, PhD, Division of Nephrology, Nanjing First Hospital, 68 Changle Road, Nanjing 210006 (China), E-Mail
                366130 Nephron Exp Nephrol 2014;128:37-45
                © 2014 S. Karger AG, Basel

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                Page count
                Figures: 7, Pages: 9
                Original Paper

                Cardiovascular Medicine, Nephrology

                IL-10, Renal ischemia-reperfusion injury, Inflammation


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