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

Abstract

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.

Endogenous interleukin-22 protects against inflammatory bowel disease but not autoimmune cholangitis in dominant negative form of transforming growth factor beta receptor type II mice

“…These data show clearly the protective role of IL-22 on cholangitis, although such effects are not clear in the dnTGF-bRII mouse model, as we demonstrated in the current study. Additionally, we should note that IL-22 also exacerbated chronic liver inflammation as exhibited, for example, in acetaminophen-induced liver injury and the hepatitis B virus (HBV) transgenic mouse model [36,37].…”

Mechanisms of Inflammatory Liver Injury and Drug-Induced Hepatotoxicity

“…Knockout of IL-22 binding protein (IL-22BP) results in increased inflammation and increased liver injury in an IL-22/CXCL10 dependent manner [77]. However, pretreatment with IL-22 reduced injury through STAT3 activation [78]. In contrast, chronic IL-22 overexpression in transgenic mice caused increased APAP-induced injury, but this is likely due to constitutive overexpression of CYP2E1 and increased metabolic activation in these animals [78].…”

Xenobiotic and Endobiotic Mediated Interactions Between the Cytochrome P450 System and the Inflammatory Response in the Liver

“…While a majority of these mechanisms on intracellular dysfunction during APAP are widely accepted in the literature, there is considerable controversy over whether or not the inflammatory cascade that follows the initial cell death mediates any portion of APAP-induced liver injury (Lawson et al, 2000; Liu et al, 2006; Jaeschke, 2008; Imaeda et al, 2009; Williams et al, 2014), even though it has been established for over 30 years that modulators of inflammation can have profound effects on CYP activity (Renton and Dickson, 1984). While it is understood that inflammation and inflammatory mediators can affect APAP metabolism through drug metabolizing enzymes such as CYP2E1, there remains substantial debate over whether or not these effects are critical to the actual pathogenesis or secondary effects (Martin-Murphy et al, 2013; Feng et al, 2014; Jaeschke et al, 2012b). …”

“…While evidence in both human patients (Williams et al, 2014) and mice (Cover et al, 2006; Lawson et al, 2000; Williams et al, 2010a; Connolly et al, 2011) does not support the hypothesis of neutrophil mediated injury, a number of papers have shown a link between metabolism of APAP and inflammation that might explain why some models show modulation of injury with therapeutic regimens designed at mitigating inflammation. Short term treatment with IL-22 protected mice from APAP induced liver injury through a STAT-3 dependent mechanism, suggesting intracellular signaling mechanisms were present that attenuated the injury (Feng et al, 2014). On the other hand IL-22 transgenic mice that chronically overexpress IL-22 had increased expression of CY2E1, which lead to an exacerbation of the injury (Feng et al, 2014).…”

“…Short term treatment with IL-22 protected mice from APAP induced liver injury through a STAT-3 dependent mechanism, suggesting intracellular signaling mechanisms were present that attenuated the injury (Feng et al, 2014). On the other hand IL-22 transgenic mice that chronically overexpress IL-22 had increased expression of CY2E1, which lead to an exacerbation of the injury (Feng et al, 2014). Similarly, Jα-18 −/− mice and CD1d −/− mice, which are largely depleted of iNKT and NKT cells, respectively, both had higher levels of injury after APAP overdose (Martin-Murphy et al, 2013).…”