Lipopolysaccharide-Induced Acute Kidney Injury Is Dependent on an IL-18 Receptor Signaling Pathway

Nozaki, Yuji; Hino, Shoichi; Ri, Jinhai; Sakai, Kenji; Nagare, Yasuaki; Kawanishi, Mai; Niki, Kaoru; Funauchi, Masanori; Matsumura, Itaru

doi:10.3390/ijms18122777

Cited by 24 publications

(23 citation statements)

References 49 publications

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“…We reported that the IL-18Rα signaling pathway has an important role in the response to TNFα and IFN-γ in CD4 + T cells among APCs [16]. In the present study, we also observed a strong reduction of the serum levels and mRNA expressions of TNFα and IFN-γ in inflamed synovium from the IL-18Rα KO mice.…”

Section: Intracellular Tnfα and Ifn-γ Staining In Cd4 + T Cells And Asupporting

confidence: 81%

“…A histopathological index was constructed by adding the scores from the evaluated joints in each animal. Immunohistochemical staining for CD4+ T cells and F4/80+ cells as the macrophages were performed on 4-μm thick formalin-fixed sections [16]. The number of positive cells was measured as the stained cell count/mm 2 per slide, and the results are Experimental schedule in wild type and IL-18Rα knock-out mice for the induction of collagen-induced arthritis (CIA).…”

Section: Histological Examinationmentioning

confidence: 99%

“…We performed a real-time PCR as described previously [16] for the measurement of the mRNA expressions of TNF, GATA3, T-bet, and 18SrRNA by using FastStart DNA Master Sybr Green I (Applied Biosystems, Foster City, CA, USA) and for the measurement of IFN-γ, IL-6, -18, -18R1 (encoding IL-18Rα), SOCS3, and 18SrRNA in the synovium using TaqMan gene (Applied Biosystems). The sequences of the primer and gene database numbers are listed in Table 1; Table 2.…”

Section: Measurements Of Mrna Expression In the Synovium By Real-timementioning

confidence: 99%

“…DBA1/J mice were mated with IL-18Rα KO mice on the C57BL/6 background to yield heterozygous F1 offspring. We intercrossed F1 mice and screened the progeny by performing a polymerase chain reaction (PCR) amplification of tail genomic DNA for the mutation and IL-18Rα using specific primers [16]. These mice were backcrossed onto the DBA/1J background for seven generations.…”

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confidence: 99%

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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: Intracellular Tnfα and Ifn-γ Staining In Cd4 + T Cells And Asupporting

confidence: 81%

Section: Histological Examinationmentioning

confidence: 99%

Section: Measurements Of Mrna Expression In the Synovium By Real-timementioning

confidence: 99%

mentioning

confidence: 99%

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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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“…A previous study has also shown that TM knockout in macrophages reduces LPS binding to macrophages and suppresses LPS-induced inflammation [41]. In accordance with our previously published report [42], the importance of TNF, IFN-γ, and IL-18 as pro-inflammatory cytokines has been demonstrated in the pathogenesis of AKI after LPS-injection, and we observed a significant reduction in the expression of these cytokines in LPS-induced AKI. In the current study, we demonstrated that rTM attenuated renal damage by reducing cytokine and apoptotic signals with the accumulation of CD4+ T-cells, CD11c+ cells, and F4/80+ cells in LPS-induced AKI.…”

Section: Discussionsupporting

confidence: 93%

Protective Effects of Recombinant Human Soluble Thrombomodulin on Lipopolysaccharide-Induced Acute Kidney Injury

Nozaki

Sakai

et al. 2020

IJMS

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Thrombomodulin (TM) is a single transmembrane, multidomain glycoprotein receptor for thrombin, and is best known for its role as a cofactor in a clinically important natural anticoagulant pathway. In addition to its anticoagulant function, TM has well-defined anti-inflammatory properties. Soluble TM levels increase significantly in the plasma of septic patients; however, the possible involvement of recombinant human soluble TM (rTM) transduction in the pathogenesis of lipopolysaccharide (LPS)-induced nephrotoxicity, including acute kidney injury (AKI), has remained unclear. Mice were injected intraperitoneally with 15 mg/kg LPS. rTM (3 mg/kg) or saline was administered to the animals before the 3 and 24 h LPS-injection. At 24 and 48 h, blood urea nitrogen, the inflammatory cytokines in sera and kidney, and histological findings were assessed. Cell activation and apoptosis signal was assessed by Western blot analysis. In this study using a mouse model of LPS-induced AKI, we found that rTM attenuated renal damage by reducing both cytokine and cell activation and apoptosis signals with the accumulation of CD4+ T-cells, CD11c+ cells, and F4/80+ cells via phospho c-Jun activations and Bax expression. These findings suggest that the mechanism underlying these effects of TM may be mediated by a reduction in inflammatory cytokine production in response to LPS. These molecules might thereby provide a new therapeutic strategy in the context of AKI with sepsis.

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The mechanistic role of cardiac glycosides in DNA damage response and repair signaling

Ainembabazi

Zhang

Turchi

2023

Cell. Mol. Life Sci.

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Cardiac glycosides (CGs) are a class of bioactive organic compounds well-known for their application in treating heart disease despite a narrow therapeutic window. Considerable evidence has demonstrated the potential to repurpose CGs for cancer treatment. Chemical modification of these CGs has been utilized in attempts to increase their anti-cancer properties; however, this has met limited success as their mechanism of action is still speculative. Recent studies have identified the DNA damage response (DDR) pathway as a target of CGs. DDR serves to coordinate numerous cellular pathways to initiate cell cycle arrest, promote DNA repair, regulate replication fork firing and protection, or induce apoptosis to avoid the survival of cells with DNA damage or cells carrying mutations. Understanding the modus operandi of cardiac glycosides will provide critical information to better address improvements in potency, reduced toxicity, and the potential to overcome drug resistance. This review summarizes recent scientific findings of the molecular mechanisms of cardiac glycosides affecting the DDR signaling pathway in cancer therapeutics from 2010 to 2022. We focus on the structural and functional differences of CGs toward identifying the critical features for DDR targeting of these agents.

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Lipopolysaccharide-Induced Acute Kidney Injury Is Dependent on an IL-18 Receptor Signaling Pathway

Cited by 24 publications

References 49 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

Protective Effects of Recombinant Human Soluble Thrombomodulin on Lipopolysaccharide-Induced Acute Kidney Injury

The mechanistic role of cardiac glycosides in DNA damage response and repair signaling

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