Interleukin-10 inhibits ischemic and cisplatin-induced acute renal injury

Deng, Joseph; Kohda, Yukimasa; Chiao, Hsi; Wang, Yuqin; Hu, Xuxhen; Hewitt, Stephen M.; Miyaji, Toru; McLeroy, Paul; Nibhanupudy, Bobby; Li, Shujun; Star, Robert A.

doi:10.1046/j.1523-1755.2001.00043.x

Cited by 361 publications

(309 citation statements)

References 64 publications

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“…Among potential candidates, we focused on IGF-1, which possesses mitogenic and antiapoptotic properties 27,31 ; TGF-␤, which is involved in tubulogenesis and in the dedifferentiation of adult tubular cells 32,33 ; and IL-10, a cytokine with anti-inflammatory activities. 34 By using specific functional blocking antibodies, we evidenced a determinant role of IGF-1 in PTEC proliferation induced by MSC. MSC constitutively expressed IGF-1 mRNA and protein, as already described, 17,35 with protein levels remarkably higher than those detected in control or cisplatin-treated PTEC.…”

Section: Discussionmentioning

confidence: 82%

Insulin-Like Growth Factor-1 Sustains Stem Cell–Mediated Renal Repair

Imberti

Morigi

Tomasoni

et al. 2007

Journal of the American Society of Nephrology

290

241

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In mice with cisplatin-induced acute kidney injury, administration of bone marrow-derived mesenchymal stem cells (MSC) restores renal tubular structure and improves renal function, but the underlying mechanism is unclear. Here, we examined the process of kidney cell repair in co-culture experiments with MSC and cisplatin-injured proximal tubular epithelial cells (PTEC). Exposure of PTEC to cisplatin markedly reduced cell viability at 4 days, but co-culture with MSC provided a protective effect by promoting tubular cell proliferation. This effect was mediated by insulin-like growth factor-1 (IGF-1), highly expressed by MSC as mRNA and protein, since blocking the growth factor's function with a specific antibody attenuated cell proliferation of PTEC. Confirming this, knocking down IGF-1 expression in MSC by small interfering-RNA also resulted in a significant decrease in PTEC proliferation and increased apoptosis. Furthermore, in the murine model of cisplatin-induced kidney injury, administering IGF-1 gene-silenced MSC limited their protective effect on renal function and tubular structure. These findings indicate that MSC exert beneficial effects on tubular cell repair in acute kidney injury by producing the mitogenic and pro-survival factor IGF-1.

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Section: Discussionmentioning

confidence: 82%

Insulin-Like Growth Factor-1 Sustains Stem Cell–Mediated Renal Repair

Imberti

Morigi

Tomasoni

et al. 2007

Journal of the American Society of Nephrology

290

241

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“…Previous studies have reported the influence of IL-10 in attenuating inflammation and kidney injury in animal models of acute GN, 17,18 CKD, 35 cisplatin nephrotoxicity, 14,36,37 and ischemic injury. 14 Further, animal studies in a variety of other disease settings have also demonstrated similar protective properties of IL-10 and have even reported that the cytokine creates an environment conducive for regenerative adult wound healing. [38][39][40][41][42] This is the first perioperative clinical study, to our knowledge, that has found a significantly protective association of a cytokine on all-cause mortality after discharge.…”

Section: Discussionmentioning

confidence: 99%

“…10,11 Accordingly, IL-6 has been suggested to exacerbate renal injury, 12,13 while IL-10 has been shown to confer protective effects. [14][15][16][17][18][19] We hypothesized that our cohort would also show these trends. Notably, a preclinical study 20 has demonstrated that IL-10 protects against renal ischemia through the induction of neutrophil gelatinase-associated lipocalin (NGAL), an established AKI biomarker that our group has previously studied.…”

mentioning

confidence: 99%

Plasma IL-6 and IL-10 Concentrations Predict AKI and Long-Term Mortality in Adults after Cardiac Surgery

Zhang

Garg

Coca

et al. 2015

Journal of the American Society of Nephrology

176

119

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Inflammation has an integral role in the pathophysiology of AKI. We investigated the associations of two biomarkers of inflammation, plasma IL-6 and IL-10, with AKI and mortality in adults undergoing cardiac surgery. Patients were enrolled at six academic centers (n=960). AKI was defined as a $50% or $0.3-mg/dl increase in serum creatinine from baseline. Pre-and postoperative IL-6 and IL-10 concentrations were categorized into tertiles and evaluated for associations with outcomes of in-hospital AKI or postdischarge all-cause mortality at a median of 3 years after surgery. Preoperative concentrations of IL-6 and IL-10 were not significantly associated with AKI or mortality. Elevated first postoperative IL-6 concentration was significantly associated with higher risk of AKI, and the risk increased in a dose-dependent manner (second tertile adjusted odds ratio [OR], 1.61 [95% confidence interval (95% CI), 1.10 to 2.36]; third tertile adjusted OR, 2.13 [95% CI, 1.45 to 3.13]). First postoperative IL-6 concentration was not associated with risk of mortality; however, the second tertile of peak IL-6 concentration was significantly associated with lower risk of mortality (adjusted hazard ratio, 0.75 [95% CI, 0.57 to 0.99]). Elevated first postoperative IL-10 concentration was significantly associated with higher risk of AKI (adjusted OR, 1.57 [95% CI, 1.04 to 2.38]) and lower risk of mortality (adjusted HR, 0.72 [95% CI, 0.56 to 0.93]). There was a significant interaction between the concentration of neutrophil gelatinase-associated lipocalin, an established AKI biomarker, and the association of IL-10 concentration with mortality (P=0.01). These findings suggest plasma IL-6 and IL-10 may serve as biomarkers for perioperative outcomes. AKI is a common complication of cardiac surgery, leading to increased morbidity and mortality. 1 Current paradigms of diagnosis and treatment are based on serum creatinine and are thus insensitive. These limitations have spurred the search for novel proteins that are involved in the process of kidney injury. 2,3 While AKI is traditionally recognized and diagnosed by renal functional impairment and structural damage, it is also an inflammatory condition. Understanding and measuring the processes of inflammation in AKI may provide unique tools for its assessment and prediction.To this end, we developed an ancillary study to our large, multicenter cohort study of adult patients

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“…Free heme is cytotoxic, and heme clearance reduces oxidative stress and apoptosis (58), which is assumed to promote resolution of inflammation. IL-10 attenuates the host response to microbial antigens, to cytokines and chemokines (21,59), to ischemia reperfusion, and to some drug-induced injuries (13,60). This limits tissue damage, but the persistence of IL-10 leads to immune suppression and to impaired pathogen clearance in infection (61).…”

Section: Was Detected (Panels A-c) Dcm/co (1-h Exposure) Caused Robumentioning

confidence: 99%

Heme Oxygenase-1 Couples Activation of Mitochondrial Biogenesis to Anti-inflammatory Cytokine Expression

Piantadosi

Withers

Bartz

et al. 2011

Journal of Biological Chemistry

231

184

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The induction of heme oxygenase-1 (HO-1; Hmox1) by inflammation, for instance in sepsis, is associated both with an anti-inflammatory response and with mitochondrial biogenesis. Here, we tested the idea that HO-1, acting through the Nfe2l2 (Nrf2) transcription factor, links anti-inflammatory cytokine expression to activation of mitochondrial biogenesis. HO-1 induction after LPS stimulated anti-inflammatory IL-10 and IL-1 receptor antagonist (IL-1Ra) expression in mouse liver, human HepG2 cells, and mouse J774.1 macrophages but blunted tumor necrosis factor-␣ expression. This was accompanied by nuclear Nfe2l2 accumulation and led us to identify abundant Nfe2l2 and other mitochondrial biogenesis transcription factor binding sites in the promoter regions of IL10 and IL1Ra compared with pro-inflammatory genes regulated by NF-〉. Mechanistically, HO-1, through its CO product, enabled these transcription factors to bind the core IL10 and IL1Ra promoters, which for IL10 included Nfe2l2, nuclear respiratory factor (NRF)-2 (Gabpa), and MEF2, and for IL1Ra, included NRF-1 and MEF2. In cells, Hmox1 or Nfe2l2 RNA silencing prevented IL-10 and IL-1Ra up-regulation, and HO-1 induction failed post-LPS in Nfe2l2-silenced cells and post-sepsis in Nfe2l2 ؊/؊ mice. Nfe2l2 ؊/؊ mice compared with WT mice, showed more liver damage, higher mortality, and ineffective CO rescue in sepsis. Nfe2l2 ؊/؊ mice in sepsis also generated higher hepatic TNF-␣ mRNA levels, lower NRF-1 and PGC-1␣ mRNA levels, and no enhancement of anti-inflammatory Il10, Socs3, or bcl-x L gene expression. These findings disclose a highly structured transcriptional network that couples mitochondrial biogenesis to counter-inflammation with major implications for immune suppression in sepsis.Early survivors of severe sepsis often develop immune suppression (1, 2) and may later die with the multiple organ dysfunction syndrome (3). A key effector of multiple organ dysfunction syndrome is the liver, which is integral to the host response, especially in infections that activate Toll-like receptor 4 and NF-〉-dependent cytokine synthesis (4). The persistence of inflammatory cytokines such as TNF-␣ and IL-1␤ perpetuates immune activation, causing tissue damage and remodeling (5) and leads to sustained production of anti-inflammatory modulators and suppressors of adaptive immunity (6, 7).These anti-inflammatory modulators include the type II cytokine IL-10, the soluble IL-1 receptor antagonist (sIL-1Ra) 2 (5), and SOCS (suppressor of cytokine signaling) proteins (8). IL-10 is widely expressed in the liver (9, 10) by Kupffer cells (11), stellate cells (12), and hepatocytes (13), where it contributes to LPS tolerance (14). The IL-10 receptor activates JAK/STAT (Janus kinase/signal transducer and activator of transcription) to block the production of TNF-␣ and other NF-〉-dependent mediators (15), the basis for its anti-inflammatory effects (16). IL-10 also suppresses mononuclear cell function (17), and IL-10 secretion by macrophages and neutrophils negatively regulates the respon...

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Interleukin-10 inhibits ischemic and cisplatin-induced acute renal injury

Abstract: IL-10 protects against renal ischemic and cisplatin-induced injury. IL-10 may act, in part, by inhibiting the maladaptive activation of genes that cause leukocyte activation and adhesion, and induction of iNOS.

Cited by 361 publications

References 64 publications

Insulin-Like Growth Factor-1 Sustains Stem Cell–Mediated Renal Repair

Insulin-Like Growth Factor-1 Sustains Stem Cell–Mediated Renal Repair

Plasma IL-6 and IL-10 Concentrations Predict AKI and Long-Term Mortality in Adults after Cardiac Surgery

Heme Oxygenase-1 Couples Activation of Mitochondrial Biogenesis to Anti-inflammatory Cytokine Expression

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