IL-18-Binding Protein Protects Against Lipopolysaccharide- Induced Lethality and Prevents the Development of Fas/Fas Ligand-Mediated Models of Liver Disease in Mice

Faggioni, Raffaella; Cattley, Russell C.; Guo, Jane; Flores, Silvia Alicia; Brown, Heather; Qi, Meiying; Su, Yin; Hill, David J.; Scully, Sheila; Chen, Ching; Brankow, David; Lewis, Jeffrey; Baikalov, Claudia; Yamane, Harvey; Meng, Shi-Yuan; Martin, Frank; Hu, Sylvia; Boone, T.; Senaldi, Giorgio

doi:10.4049/jimmunol.167.10.5913

Cited by 106 publications

(75 citation statements)

References 52 publications

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“…Given that IL-18 induces IL-13 production in both NK cells and T cells in synergy with and that in vivo administration of IL-18 increases serum IgE levels and splenocyte production of Th2 cytokines [20], IL-18 seemed a likely candidate for driving IL-13 production during this IL-4/B7-independent protective immune response to T. muris. To address this, we used IL-18BP-Fc, which has been shown to completely block LPSinduced IFN-c production in vivo [31]. Our findings showed that blocking IL-18 in vivo abrogated IL-13-dependent host protection following B7 and IFN-c blockade, indicating that IL-18 induces IL-13 production under these conditions.…”

Section: Discussionmentioning

confidence: 94%

“…To address this, we used IL-18BP-Fc, which has been shown to completely block LPSinduced IFN-c production in vivo [31]. Our findings showed that blocking IL-18 in vivo abrogated IL-13-dependent host protection following B7 and IFN-c blockade, indicating that IL-18 induces IL-13 production under these conditions.…”

Section: Discussionmentioning

confidence: 94%

“…We were interested in examining whether IL-18 also plays a role in the in vivo IL-13-mediated resistance to T. muris that occurs following inhibition of B7 and IFN-c. To address this possibility, we used IL-18 binding protein (IL-18BP) [31] to block IL-18 function in vivo. WT BALB/c mice were inoculated with T. muris eggs.…”

Section: Increases In Il-13 Production Remain Cd4 + T Cell-dependentmentioning

confidence: 99%

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IL‐18 stimulates IL‐13‐mediated IFN‐γ‐sensitive host resistance in vivo

Liu

Whitmire

et al. 2006

Eur J Immunol

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IL-4 and IL-13 are up-regulated during in vivo responses to many nematode parasites, but increasing evidence suggests that increases in IL-13 can also occur independently of the IL-4-dominant Th2 response. Blocking B7 after Trichuris muris inoculation inhibits resistance and IL-4 elevations, instead resulting in an IFN-c-dominant response associated with susceptibility. However, blocking IFN-c under these conditions restores IL-13-dependent resistance. In this study, we examined the mechanism of IL-13 upregulation and associated protection during this in vivo immune response. CD4 + T cells and DX5 + TCR -cells were identified as the major producers of IL-13, and the DX5 + TCRcells were phenotyped as NK cells, since they expressed CD11b, IL-2Rb and Ly49C but not c-kit or FceRI. NK cell-derived IL-13 elevations were T cell-dependent, as CD4 + T cell depletion blocked IL-13 production by mesenteric lymph node cells and induced susceptibility. IL-13 expression was increased independently of IL-12; however, blocking IL-18 function inhibited IL-13 production and increased susceptibility. These results indicate that CD4 + T cells and NK cells are the major sources of IL-13 during the in vivo Th1 response induced by B7 blockade and that under these conditions, IL-18 is specifically required for the in vivo up-regulation of IL-13 production and associated host protection. IntroductionThe host protective response that develops following infection varies greatly with the particular pathogen. The type 2 immune response, associated with high levels of IL-4, IL-13 and other Th2 cytokines, provides protection against intestinal nematode parasites [1-3], while type 1 immunity, associated with an IFNc-dominant response, mediates resistance against many viruses and bacteria [4,5]. The events that lead to the development of type 1 and type 2 immunity are generally thought to be distinct, and as each response matures, production of characteristic cytokines can down-regulate the reciprocal response, resulting in further polarization.Typically, type 2 responses leading to resistance require the development of IL-4-producing effector CD4 + T cells, which then utilize autocrine IL-4 for their rapid expansion [3]. These Th2 cells mediate worm expulsion through their production of Th2 cytokines, with IL-4 and IL-13 being particularly important for the expulsion of gastrointestinal nematode parasites [1,2]. The development and expansion of IL-4-producing T cells is preferentially dependent on B7 costimulatory molecules [6,7], and in a number of infectious diseases, B7 blockade can actually deviate a Th2 response to an IFN-c-dominant Th1 response [8,9]. In the Th2 cell differentiation model just described, blockade of IL-4 production with B7 antagonists would be expected to also inhibit IL-13 production. However, other studies suggest that under certain circumstances IL-4 and IL-13 are regulated independently, and certain signaling pathways involving c-maf [10] and can differentially regulate these two cytokines. Consistent with these fin...

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 94%

Section: Increases In Il-13 Production Remain Cd4 + T Cell-dependentmentioning

confidence: 99%

See 1 more Smart Citation

IL‐18 stimulates IL‐13‐mediated IFN‐γ‐sensitive host resistance in vivo

Liu

Whitmire

et al. 2006

Eur J Immunol

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“…In the 30 µg/kg group, mortality was 37% at 48HPE but 25% at 60 HPE, suggesting that the critical hepatotoxicity effect might have saturated by 48 HPE. In comparison with various doses for inducing death in mouse study (85 [20], 300 [4,5], and 500 [15] µg/kg PEA in C57BL/6; 85 [18)] and 300 [26] µg/kg in BALB/c; 115 µg/kg [16] in Swiss; and 600 µg/kg [1] in Mttp ∆/∆ (background: 50% 129/SvJae and 50% C57BL/6)). These were 8-fold differences among the same species animals that appeared to be confusing to researchers.…”

Section: Discussionmentioning

confidence: 99%

“…injection have not been convinced. These are wide ranges running from 85 [20,26], 115 [16], 300 [4,5], 500 [15], and 600 µg/kg [1]. As rats are the most common rodent laboratory animals used in hepatotoxicologic assessment, we initiated the study for: 1) Establish a new model using rats for the purpose of liver toxicity investigation, 2) Compare doses in PEA-treated rats with the PEA-treated mice dose for hepatotoxicity study, 3) Detect liver alterations at different doses and time points, and 4) Investigate the possible playing roles of cytokines and immuno-regulators in the PEA-induced hepatotoxicity.…”

mentioning

confidence: 99%

Pseudomonas aeruginosa Exotoxin A-Induced Hepatotoxicity: An Animal Model in Rats

Chiu

Chen²,

Chuang

et al. 2009

The Journal of Veterinary Medical Science

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ABSTRACT. Pseudomonas aeruginosa Exotoxin A (PEA) has been generally used to induce liver injury in mice for experimental study. No PEA-induced hepatotoxicity study has ever been conducted in rats, although rats are the most common rodents used in toxicologic bioassay and pharmacological evaluation. The present study was conducted in male Wistar rats that were injected (i.v.) with PEA at doses of 0, 10, 20, 30 or 40 µg/kg body weight and evaluated at 12, 24, 36, 48 and 60 hr post-exposure (HPE). Rats exposed to PEA at 40 µg/kg died before 36 HPE, and the mortality was dose and time dependent. Liver injury was noted as increases in serum enzymes, along with alterations of liver histology in the 40 µg/kg group at 12 HPE. TUNEL-positive staining indicative of hepatocyte apoptosis was observed in the 20 µg/kg group at 12 HPE. Significant levels of DNA fragmentation ladder were observed in the 30 µg/kg group starting at 24 HPE. Serum levels of TNF-α was increased in the 30 and 40 µg/kg groups at 48 and 24 HPE, respectively. Other cytokines, such as IL-2, IL-6, and IL-10 were also increased at various doses and times. Furthermore, the elevated serum heaptic index levels decreased significantly by dexamethasone pretreatment. In contrast, these markers were exacerbated by co-administration of a non-toxic dose LPS. In overall evaluation, the PEA-induced liver injury can be used as a model for study of hyperimmune-mediated hepatotoxicity.

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Interleukin‐18 signaling promotes activation of hepatic stellate cells in mouse liver fibrosis

Knorr

Kaufmann

Inzaugarat³

et al. 2022

Hepatology

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Background and Aims: Nucleotide‐binding oligomerization domain‐like receptor‐family pyrin domain‐containing 3 (NLRP3) inflammasome activation has been shown to result in liver fibrosis. Mechanisms and downstream signaling remain incompletely understood. Here, we studied the role of IL‐18 in hepatic stellate cells (HSCs), and its impact on liver fibrosis. Approach and Results: We observed significantly increased serum levels of IL‐18 (128.4 pg/ml vs. 74.9 pg/ml) and IL‐18 binding protein (BP; 46.50 ng/ml vs. 15.35 ng/ml) in patients with liver cirrhosis compared with healthy controls. Single cell RNA sequencing data showed that an immunoregulatory subset of murine HSCs highly expresses Il18 and Il18r1. Treatment of cultured primary murine HSC with recombinant mouse IL‐18 accelerated their transdifferentiation into myofibroblasts. In vivo, IL‐18 receptor‐deficient mice had reduced liver fibrosis in a model of fibrosis induced by HSC‐specific NLRP3 overactivation. Whole liver RNA sequencing analysis from a murine model of severe NASH‐induced fibrosis by feeding a choline‐deficient, L‐amino acid‐defined, high fat diet showed that genes related to IL‐18 and its downstream signaling were significantly upregulated, and Il18 −/− mice receiving this diet for 10 weeks showed protection from fibrotic changes with decreased number of alpha smooth muscle actin‐positive cells and collagen deposition. HSC activation triggered by NLRP3 inflammasome activation was abrogated when IL‐18 signaling was blocked by its naturally occurring antagonist IL‐18BP. Accordingly, we observed that the severe inflammatory phenotype associated with myeloid cell‐specific NLRP3 gain‐of‐function was rescued by IL‐18BP. Conclusions: Our study highlights the role of IL‐18 in the development of liver fibrosis by its direct effect on HSC activation identifying IL‐18 as a target to treat liver fibrosis.

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IL-18-Binding Protein Protects Against Lipopolysaccharide- Induced Lethality and Prevents the Development of Fas/Fas Ligand-Mediated Models of Liver Disease in Mice

Cited by 106 publications

References 52 publications

IL‐18 stimulates IL‐13‐mediated IFN‐γ‐sensitive host resistance in vivo

IL‐18 stimulates IL‐13‐mediated IFN‐γ‐sensitive host resistance in vivo

Pseudomonas aeruginosa Exotoxin A-Induced Hepatotoxicity: An Animal Model in Rats

Interleukin‐18 signaling promotes activation of hepatic stellate cells in mouse liver fibrosis

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