Protective effect and mechanism of IL-10 on renal ischemia–reperfusion injury

Sakai, Kenji; Nozaki, Yuji; Murao, Yoshinori; Yano, Tomohiro; Ri, Jinhai; Niki, Kaoru; Kinoshita, Koji; Funauchi, Masanori; Matsumura, Itaru

doi:10.1038/s41374-018-0162-0

Cited by 59 publications

(48 citation statements)

References 41 publications

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“…In a mouse model of acute kidney injury (AKI), our findings indicated that IL-18Rα may mediate anti-inflammatory responses through SOCS1 and/or -3 in cisplatin-induced AKI [19]. Our later investigation showed that IL-18Rα also mediates apoptosis in a murine model of ischemia/reperfusion injury [21]. In a mouse model of lupus (autoimmune nephritis), we observed that MRL-Faslpr mice (well known as a lupus model) cross-bred with mice deficient in IL-18Rα had a better survival rate and lessened nephritis because of their reduced levels of autoantibodies [15].…”

Section: Discussionmentioning

confidence: 81%

Inhibition of the IL-18 Receptor Signaling Pathway Ameliorates Disease in a Murine Model of Rheumatoid Arthritis

Nozaki

Sakai

et al. 2019

Cells

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Interleukin (IL)-18 expression in synovial tissue correlates with the severity of joint inflammation and the levels of pro-inflammatory cytokines. However, the role of the IL-18/IL-18 receptor-alpha (Rα) signaling pathway in autoimmune arthritis is unknown. Wild-type (WT) and IL-18Rα knockout (KO) mice were immunized with bovine type II collagen before the onset of arthritis induced by lipopolysaccharide injection. Disease activity was evaluated by semiquantitative scoring and histologic assessment. Serum inflammatory cytokine and anticollagen antibody levels were quantified by an enzyme-linked immunosorbent assay. Joint cytokine and matrix metalloproteinases-3 levels were determined by a quantitative polymerase chain reaction. Splenic suppressors of cytokine signaling (SOCS) were determined by Western blot analysis as indices of systemic immunoresponse. IL-18Rα KO mice showed lower arthritis and histological scores in bone erosion and synovitis due to reductions in the infiltration of CD4+ T cells and F4/80+ cells and decreased serum IL-6, -18, TNF, and IFN-γ levels. The mRNA expression and protein levels of SOCS3 were significantly increased in the IL-18Rα KO mice. By an up-regulation of SOCS, pro-inflammatory cytokines were decreased through the IL-18/IL-18Rα signaling pathway. These results suggest that inhibitors of the IL-18/IL-18Rα signaling pathway could become new therapeutic agents for rheumatoid arthritis.Cells 2020, 9, 11 2 of 18 occurring IL-18 binding protein (IL-18BP) or a systemic neutralization by specific antibodies results in the amelioration of CIA, associated with reduced inflammation and cartilage erosion [6][7][8].The inhibition of cytokine signaling by the suppressors of cytokine signaling (SOCS) family constitutes a major negative feedback mechanism to prevent runaway inflammation. The transcription of SOCS proteins is rapidly upregulated in cells stimulated with cytokines. The SOCS then reduce the impact of cytokines by interacting with Janus kinases (JAKs) and by other mechanisms [9]. The roles of SOCS1 and −3 are underscored by the higher levels of the proinflammatory p38α and p38β mitogen-activated protein kinases (MAPKs) observed in IL-18Rα-deficient mouse embryonic fibroblasts (MEFs) compared to wild-type (WT) and IL-18-deficient MEFs. Since both SOCS1 [10][11][12] and SOCS3 [13,14] interfere with the IL-1/TLR-MAPK/nuclear factor-kappa (NF-κ)B pathway signaling, the increase in activity of these kinases in IL-18Rα-deficient cells may be due to a lesser degree of inhibition resulting from the reduced levels of both of these SOCS family members.In the present study, we confirmed that IL-18Rα was aberrantly expressed in the lymph nodes (LN) and splenocytes of mice with lipopolysaccharide (LPS)-induced arthritis. We hypothesized that if arthritis becomes hyper-responsive to LPS, which is a component of Gram-negative bacteria, this hyper-responsiveness may increase the levels of circulating inflammatory cytokines such as TNF, interferon-gamma (IFN-γ), and IL-6 and result in the blocking ...

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Section: Discussionmentioning

confidence: 81%

Inhibition of the IL-18 Receptor Signaling Pathway Ameliorates Disease in a Murine Model of Rheumatoid Arthritis

Nozaki

Sakai

et al. 2019

Cells

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“…In this study, we found the numbers of inflammatory cells were suppressed in apelin-treated mice at day 1. It has been reported that IL-10, bFGF and TGF-β prevent tissue damage after I/R injury [38][39][40] . We demonstrated that qPCR analysis revealed that apelin administration enhanced the expression of these tissue protective cytokines and growth factors, such as IL-10, bFGF and TGF-β in I/R site, however, further studies will be needed to clarify the precise mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Apelin/APJ signaling suppresses the pressure ulcer formation in cutaneous ischemia-reperfusion injury mouse model

Yamazaki

Sekiguchi

Uchiyama

et al. 2020

Sci Rep

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Several studies have demonstrated potential roles for apelin/ApJ signaling in the regulation of oxidative stress associated with ischemia-reperfusion (i/R) injury in several organs. objective was to assess the role of apelin/ApJ signaling in the development of pressure ulcers (pUs) formation after cutaneous i/R injury in mice. We identified that cutaneous I/R injury increased the expression of apelin in the skin at I/R site. Administration of apelin significantly inhibited the formation of PUs. The reductions of blood vessels, hypoxic area and apoptosis in i/R site were inhibited by apelin injection. oxidative stress signals in OKD48 mice and the expressions of oxidative stress related genes in the skin were suppressed by apelin injection. H 2 o 2 -induced intracellular ROS and apoptosis in endothelial cells and fibroblasts were suppressed by apelin in vitro. Furthermore, MM07, biased agonist of APJ, also significantly suppressed the development of PUs after cutaneous I/R, and the inhibitory effect of MM07 on PUs formation was higher than that in apelin. We conclude that apelin/ApJ signaling may inhibit cutaneous i/R injuryinduced pUs formation by protecting the reduction of vascularity and tissue damage via suppression of oxidative stress. Exogenous application of apelin or MM07 might have therapeutic potentials against the development of pUs.Pressure ulcers (PUs) are one of the common skin diseases which usually occur elder people and patients with perceptual or movement disorder. In addition, the patients with PUs sometimes cause fatal outcome by local and systemic infections. There has long been considered that the pathogenesis of PUs was associated with tissue damage caused by external force and ischemia. However, there has been increasing evidence that cutaneous ischemia-reperfusion (I/R) is important in the pathogenesis of PUs 1-3 . I/R injury is defined as cellular injury caused by the reperfusion of blood to previously ischemic tissue 4,5 . It is described that reperfusion of blood into the hypoxic tissue triggers off adverse events, including thrombosis and capillary narrowing which lead to vasculopathy, infiltration of inflammatory cells, production of proinflammatory cytokines and the apoptosis of resident cells and necrosis of tissues 6 . I/R injury causes multiple diseases, such as vascular infarction or spasm of brain, heart, kidney and skin. Reactive oxygen species (ROS), such as H 2 O 2 and NO, are also known as a key player that exacerbate the tissues damage caused by I/R injury 7 .Apelin, an endogenous ligand of G protein-coulpled receptor APJ (putative receptor protein related to the angiotensin receptor AT1) 8,9 has multiple functions in the regulation of cardiovascular hemostasis, angiogenesis and adipose tissue function via apelin/APJ signaling 10-13 . APJ is expressed ubiquitously, especially in endothelial cells and vascular smooth muscle cells 8,9,11,12 . Furthermore, recent studies demonstrated that apelin/APJ signaling prevented oxidative stress, resulting in the inhibition of diabetic...

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“…Many lung transplant recipients receive IL-2R blockade during induction therapy, which may be deleterious to outcomes as it may inhibit the ability of Tregs to facilitate tolerance induction. 171 In a pilot trial of early IL-10 therapy following human kidney transplantation, IL-10 therapy was found to be safe and associated with a reduction in TNF-α. IL-10, for example, is known to induce Foxp3 expression and Treg formation in both humans 169 and mouse models of disease.…”

Section: Future D Irec Ti On Smentioning

confidence: 99%

“…170 While the effects on IL-10 on Tregs posttransplantation remains unknown, it has been shown to suppress the release of proinflammatory cytokines and ischemia-reperfusion injury in a mouse model of kidney transplantation. 171 In a pilot trial of early IL-10 therapy following human kidney transplantation, IL-10 therapy was found to be safe and associated with a reduction in TNF-α. 172 Interestingly, methods have been developed that allow for IL-10 localization to inflamed tissues which holds great relevance in the setting of acute rejection episodes; this therapy is undergoing Phase 2 trials in rheumatoid arthritis.…”

Section: Future D Irec Ti On Smentioning

confidence: 99%

The emerging role of regulatory T cells following lung transplantation

Gauthier

Harrison

Krupnick

et al. 2019

Immunological Reviews

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Regulatory T cells (Treg) have proven to be a powerful immunologic force in nearly every organ system and hold therapeutic potential for a wide range of diseases. Insights gained from non‐transplant pathologies, such as infection, cancer, and autoimmunity, are now being translated to the field of solid organ transplantation, particularly for livers and kidneys. Recent insights from animal models of lung transplantation have established that Tregs play a vital role in suppressing rejection and facilitating tolerance of lung allografts, and such discoveries are being validated in human studies and preclinical trials. Given that long‐term outcomes following lung transplantation remain profoundly limited by chronic rejection, Treg therapy holds the potential to significantly improve patient outcomes and should be aggressively investigated.

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Protective effect and mechanism of IL-10 on renal ischemia–reperfusion injury

Cited by 59 publications

References 41 publications

Inhibition of the IL-18 Receptor Signaling Pathway Ameliorates Disease in a Murine Model of Rheumatoid Arthritis

Inhibition of the IL-18 Receptor Signaling Pathway Ameliorates Disease in a Murine Model of Rheumatoid Arthritis

Apelin/APJ signaling suppresses the pressure ulcer formation in cutaneous ischemia-reperfusion injury mouse model

The emerging role of regulatory T cells following lung transplantation

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