Application of Interleukin-22 Mediates Protection in Experimental Acetaminophen-Induced Acute Liver Injury

Scheiermann, Patrick; Bachmann, Michael; Goren, Itamar; Zwißler, Bernhard; Pfeilschifter, Josef; Mühl, Heiko

doi:10.1016/j.ajpath.2012.12.010

Cited by 64 publications

(85 citation statements)

References 36 publications

(40 reference statements)

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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%

“…Our data demonstrate that the injection of a single dose of IL-22 has a prophylactic protective effect against AILI, which is in agreement with a previous report (34). The protective effect of acute IL-22 treatment on AILI is mediated through STAT3 activation because the disruption of hepatic STAT3 abolished the protective function of acute IL-22 treatment.…”

Section: Introductionsupporting

confidence: 94%

“…These include STAT1, STAT5, ERK1/2, and AKT (51). During the preparation of our manuscript, Scheiermann et al reported that the pretreatment of mice with IL-22 prevented AILI; however, the underlying mechanisms were not elucidated (34). In the current study, we demonstrated that the protective effect of IL-22 is abrogated in liver-specific STAT3 KO mice.…”

Section: Discussionmentioning

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: Introductionsupporting

confidence: 94%

Section: Discussionmentioning

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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“…STAT3 was reported to be involved in APAP-induced hepatotoxicity, where IL-22, a STAT3-activating cytokine, was shown to attenuate APAP-induced liver injury [20]. Thus, expression of mRNAs encoded by the STAT3 target genes Socs3 , Fga , Fgb and Fgg were assessed.…”

Section: Resultsmentioning

confidence: 99%

“…Recently, prophylactic injection of IL-22, a STAT3-activating cytokine, significantly reduced hepatocyte damage due to APAP, suggesting a protective role of STAT3 [20]. However, forced expression of STAT3 target gene Socs 3 in T cells was reported to exacerbate APAP-induced hepatotoxicity [29].…”

Section: Discussionmentioning

confidence: 99%

Saikosaponin d protects against acetaminophen-induced hepatotoxicity by inhibiting NF-κB and STAT3 signaling

Liu

Tanaka

Sun

et al. 2014

Chemico-Biological Interactions

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Overdose of acetaminophen (APAP) can cause acute liver injury that is sometimes fatal, requiring efficient pharmacological intervention. The traditional Chinese herb Bupleurum falcatum has been widely used for the treatment of several liver diseases in eastern Asian countries, and saikosaponin d (SSd) is one of its major pharmacologically-active components. However, the efficacy of Bupleurum falcatum or SSd on APAP toxicity remains unclear. C57BL/6 mice were administered SSd intraperitoneally once daily for five days, followed by APAP challenge. Biochemical and pathological analysis revealed that mice treated with SSd were protected against APAP-induced hepatotoxicity. SSd markedly suppressed phosphorylation of nuclear factor kappa B (NF-kB) and signal transducer and activator of transcription 3 (STAT3) and reversed the APAP-induced increases in the target genes of NF-kB, such as pro-inflammatory cytokine Il6 and Ccl2, and those of STAT3, such as Socs3, Fga, Fgb and Fgg. SSd also enhanced the expression of the anti-inflammatory cytokine Il10 mRNA. Collectively, these results demonstrate that SSd protects mice from APAP-induced hepatotoxicity mainly through down-regulating NF-kB- and STAT3-mediated inflammatory signaling. This study unveils one of the possible mechanisms of hepatoprotection caused by Bupleurum falcatum and/or SSd.

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Cooperation between the bacterial‐derived short‐chain fatty acid butyrate and interleukin‐22 detected in human Caco2 colon epithelial/carcinoma cells

et al. 2016

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By generating biologically active factors luminal microbiota shape the intestinal micro-milieu thereby regulating pathological processes such as inflammation and carcinogenesis. Preclinical data suggest that bacterial-derived butyrate and the signal transducer and activator of transcription (STAT)-3 activating cytokine interleukin (IL)-22 display concordant protective properties at the inflamed colonic epithelium. Herein, biochemical cooperation between the short-chain fatty acid butyrate and IL-22 was investigated by focusing on human Caco2 colon epithelial/carcinoma cells. We report that physiological levels of butyrate enhance IL-22 signaling thereby enforcing expression of the prototypic STAT3-downstrean target genes α1-antichymotrypsin and suppressor of cytokine signaling (SOCS)-3. A dual mode of butyrate action on the IL-22/STAT3 axis was identified. Butyrate acted by upregulating IL-22R1, the decisive chain of the heterodimeric IL-22 receptor, and, independent from that, has the potential to directly amplify STAT3-mediated gene activation as detected by chromatin immunoprecipitation analysis of STAT3 binding to the SOCS3 promoter. Since trichostatin A acted similarly, inhibition of histone deacetylases is likely at the root of these butyrate biological properties. The mutual benefit gained from interactions between the host and commensal intestinal bacteria-derived factors is an expanding field of research beginning to affect clinical practice. Data presented herein propose a supportive and fine-tuning role for butyrate in IL-22 signaling that might be therapeutically exploited by local butyrate administration or by increasing its bacterial production in the context of a fiber-rich diet. © 2016 BioFactors, 43(2):283-292, 2017.

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Application of Interleukin-22 Mediates Protection in Experimental Acetaminophen-Induced Acute Liver Injury

Cited by 64 publications

References 36 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

Saikosaponin d protects against acetaminophen-induced hepatotoxicity by inhibiting NF-κB and STAT3 signaling

Cooperation between the bacterial‐derived short‐chain fatty acid butyrate and interleukin‐22 detected in human Caco2 colon epithelial/carcinoma cells

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