Hepatoprotective effects of IL-22 on fulminant hepatic failure induced by d-galactosamine and lipopolysaccharide in mice

Xing, Weiwei; Zou, Minji; Liu, Shen; Xu, Tao; Gao, Jie; Xu, Da-Zhong

doi:10.1016/j.cyto.2011.07.022

Cited by 52 publications

(44 citation statements)

References 26 publications

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“…The protective role of IL-22 in various models of acute liver injury including AILI has been well documented (26–31, 34); in this study, we also confirmed that treatment with a single dose of IL-22 prevents AILI. As shown in Fig.…”

Section: Resultssupporting

confidence: 87%

“…IL-22 is mainly produced by Th17 cells, natural killer (NK) and NKT cells and plays critical roles in controlling bacterial infection and tissue repair (23–25). The hepatoprotective effects of IL-22 have been well documented in various mouse models (26–31). Clinical trials evaluating the therapeutic potential of recombinant IL-22 on alcoholic hepatitis and acute liver failure are under consideration.…”

Section: Introductionmentioning

confidence: 99%

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Acute and Chronic Effects of IL-22 on Acetaminophen-Induced Liver Injury

Feng

Wang

et al. 2014

The Journal of Immunology

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Acetaminophen (APAP)-induced liver injury (AILI) accounts for half of the acute liver failure cases in the United States. A better understanding of the underlying mechanisms of AILI is necessary for the development of novel antidotes. We found that pretreatment with interleukin-22 (IL-22) protected mice from APAP-mediated hepatotoxicity. The protection was dependent on STAT3, as IL-22 failed to reduce APAP hepatotoxicity in liver-specific STAT3 knockout mice. In contrast to the acute exposure to IL-22, the endogenous chronic overexpression of IL-22 in IL-22 transgenic (TG) mice or IL-22 adenovirus treatment for 6 weeks resulted in a markedly increased susceptibility to AILI. Furthermore, the hepatic expression levels of Cyp2E1 and Cyp1A2 were much higher in IL-22TG mice. Ablation of Cyp2E1 but not hepatic STAT3 abolished AILI and protein-adduct formation in IL-22TG mice. Finally, hepatic expression of HNF1α, a transcriptional factor that is known to control Cyp2E1 expression, was elevated in IL-22TG mice compared with wild-type mice. Upregulation of hepatic Cyp2E1 was only observed in mice with constitutive overexpression of IL-22 but not with short-term treatment with one dose of IL-22 or multiple doses of IL-22 for two weeks. In conclusion, short-term acute IL-22 exposure protects mice against AILI through STAT3 activation; however, chronic constitutive overexpression of IL-22 exacerbates AILI by increasing Cyp2E1 and toxic reactive APAP metabolite production. These findings may not only enhance our understanding of the effects of chronic inflammation on AILI in patients with liver disease but also helpful to identify novel therapeutic targets for the treatment of AILI.

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Section: Resultssupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Acute and Chronic Effects of IL-22 on Acetaminophen-Induced Liver Injury

Feng

Wang

et al. 2014

The Journal of Immunology

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“…Its receptor is not present on hematopoietic cells but on tissues, particularly epithelial cells such as gut epithelial cells, keratinocytes, and hepatocytes (Wolk and Sabat, 2006), and it has an important cyto-protective function contributing to tissue and cell repair (Sonnenberg et al, 2011). Given our findings of increased liver damage in P. chabaudi infection in IL-22 KO mice, its ability to protect hepatocytes during liver inflammation (Radaeva et al, 2004; Xing et al, 2011; Xu et al, 2011) is of particular relevance.…”

Section: Discussionmentioning

confidence: 82%

“…These T C 17 cells are defined by the expression of CD161 and a pattern of molecules consistent with T H 17 differentiation including IL-17 and IL-22 cytokines. In addition, T C 17 cells are markedly enriched in tissue samples, such as liver, and maybe associated with protection against human Hepatitis C pathology (Billerbeck et al, 2010), in line with the known hepato-protective function of IL-22 (Radaeva et al, 2004; Xing et al, 2011; Xu et al, 2011). In our mouse model of malaria, however, we did not detect any IL-17/IL-22 double-producing cells.…”

Section: Discussionmentioning

confidence: 94%

IL-22 Protects Against Liver Pathology and Lethality of an Experimental Blood-Stage Malaria Infection

Mastelic¹,

Rosário²,

Veldhoen³

et al. 2012

Front. Immun.

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The host response following malaria infection depends on a fine balance between levels of pro-inflammatory and anti-inflammatory mediators resulting in the resolution of the infection or immune-mediated pathology. Whilst other components of the innate immune system contribute to the pro-inflammatory milieu, T cells play a major role. For blood-stage malaria, CD4+ and γδ T cells are major producers of the IFN-γ that controls parasitemia, however, a role for TH17 cells secreting IL-17A and other cytokines, including IL-17F and IL-22 has not yet been investigated in malaria. TH17 cells have been shown to play a role in some protozoan infections, but they also are a source of pro-inflammatory cytokines known to be involved in protection or pathogenicity of infections. In the present study, we have investigated whether IL-17A and IL-22 are induced during a Plasmodium chabaudi infection in mice, and whether these cytokines contribute to either protection or to pathology induced during the infection. Although small numbers of IL-17- and IL-22-producing CD4 T cells are induced in the spleens of infected mice, a more pronounced induction is observed in the liver, where increases in mRNA for IL-17A and, to a lesser extent, IL-22 were observed and CD8+ T cells, rather than CD4 T cells, are a major source of these cytokines in this organ. Although the lack of IL-17 did not affect the outcome of infection or pathology, lack of IL-22 resulted in 50% mortality within 12 days after infection with significantly greater weight loss at the peak of infection and significant increase in alanine transaminase in the plasma in the acute infection. As parasitemias and temperature were similar in IL-22 KO and wild-type control mice, our observations support the idea that IL-22 but not IL-17 provides protection from the potentially lethal effects of liver damage during a primary P. chabaudi infection.

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“…Ki et al[12] demonstrated an antioxidant role of IL-22 in ALF, indicated by the upregulation of antioxidant proteins metallothionein I/II. Xing et al[13] established an animal model of chronic alcoholic hepatitis using high-fat diet, carbonyl and Fe(III) complex factors. Based on this model, they found that IL-22 reduced liver lipid peroxidation, restored the level of GSH, and inhibited oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

Antioxidant axis Nrf2-keap1-ARE in inhibition of alcoholic liver fibrosis by IL-22

2017

WJG

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AIMTo explore the effect of interleukin (IL)-22 on in vitro model of alcoholic liver fibrosis hepatic stellate cells (HSCs), and whether this is related to regulation of Nrf2-keap1-ARE.METHODSHSC-T6 cells were incubated with 25, 50, 100, 200 and 400 μmol/L acetaldehyde. After 24 and 48 h, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to detect proliferation of HSCs to choose the best concentration and action time. We used the optimal concentration of acetaldehyde (200 μmol/L) to stimulate HSCs for 24 h, and treated the cells with a final concentration of 10, 20 or 50 ng/mL IL-22. The cell proliferation rate was detected by MTT assay. The cell cycle was analyzed by flow cytometry. The expression of nuclear factor-related factor (Nrf)2 and α-smooth muscle antigen was detected by western blotting and immunocytochemistry. The levels of malondialdehyde (MDA) and glutathione (GSH) were measured by spectrophotometry.RESULTSIn the MTT assay, when HSCs were incubated with acetaldehyde, activity and proliferation were higher than in the control group, and were most obvious after 48 h treatment with 200 μmol/L acetaldehyde. The number of cells in G0/G1 phases was decreased and the number in S phase was increased in comparison with the control group. When treated with different concentrations of IL-22, HSC-T6 cell activity and proliferation rate were markedly decreased in a dose-dependent manner, and cell cycle progression was arrested from G1 to S phase. Western blotting and immunocytochemistry demonstrated that expression of Nrf2 total protein was not significantly affected. Expression of Nrf2 nuclear protein was low in the control group, increased slightly in the model group (or acetaldehyde-stimulated group), and increased more obviously in the IL-22 intervention groups. The levels of MDA and GSH in the model group were significantly enhanced in comparison with those in the control group. In cells treated with IL-22, the MDA level was attenuated but the GSH level was further increased. These changes were dose-dependent.CONCLUSIONIL-22 inhibits acetaldehyde-induced HSC activation and proliferation, which may be related to nuclear translocation of Nrf2 and increased activity of the antioxidant axis Nrf2-keap1-ARE.

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Hepatoprotective effects of IL-22 on fulminant hepatic failure induced by d-galactosamine and lipopolysaccharide in mice

Cited by 52 publications

References 26 publications

Acute and Chronic Effects of IL-22 on Acetaminophen-Induced Liver Injury

Acute and Chronic Effects of IL-22 on Acetaminophen-Induced Liver Injury

IL-22 Protects Against Liver Pathology and Lethality of an Experimental Blood-Stage Malaria Infection

Antioxidant axis Nrf2-keap1-ARE in inhibition of alcoholic liver fibrosis by IL-22

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