Acute and chronic effects of IL-22 on acetaminophen-induced liver injury

Dechun Feng, Yan Wang, Hua Wang, Honglei Weng, Xiaoni Kong, Brittany V. Martin-Murphy, Yongmei Li, Ogyi Park, Steven Dooley, Cynthia Ju, Bin Gao

Research output: Contribution to journalArticle

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 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 wk resulted in a markedly increased susceptibility to AILI. Furthermore, the hepatic expression levels of cytochrome 2E1 (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 HNF-1α, 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 2 wk. 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 are also helpful to identify novel therapeutic targets for the treatment of AILI.

Original languageEnglish (US)
Pages (from-to)2512-2518
Number of pages7
JournalJournal of Immunology
Volume193
Issue number5
DOIs
StatePublished - Sep 1 2014
Externally publishedYes

Fingerprint

Acetaminophen
Liver
Wounds and Injuries
interleukin-22
Antidotes
Acute Liver Failure
Poisons
Therapeutics
Cytochromes
Adenoviridae
Knockout Mice
Transgenic Mice
Interleukin-2
Liver Diseases
Up-Regulation
Inflammation

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

Cite this

Feng, D., Wang, Y., Wang, H., Weng, H., Kong, X., Martin-Murphy, B. V., ... Gao, B. (2014). Acute and chronic effects of IL-22 on acetaminophen-induced liver injury. Journal of Immunology, 193(5), 2512-2518. https://doi.org/10.4049/jimmunol.1400588

Acute and chronic effects of IL-22 on acetaminophen-induced liver injury. / Feng, Dechun; Wang, Yan; Wang, Hua; Weng, Honglei; Kong, Xiaoni; Martin-Murphy, Brittany V.; Li, Yongmei; Park, Ogyi; Dooley, Steven; Ju, Cynthia; Gao, Bin.

In: Journal of Immunology, Vol. 193, No. 5, 01.09.2014, p. 2512-2518.

Research output: Contribution to journalArticle

Feng, D, Wang, Y, Wang, H, Weng, H, Kong, X, Martin-Murphy, BV, Li, Y, Park, O, Dooley, S, Ju, C & Gao, B 2014, 'Acute and chronic effects of IL-22 on acetaminophen-induced liver injury', Journal of Immunology, vol. 193, no. 5, pp. 2512-2518. https://doi.org/10.4049/jimmunol.1400588
Feng D, Wang Y, Wang H, Weng H, Kong X, Martin-Murphy BV et al. Acute and chronic effects of IL-22 on acetaminophen-induced liver injury. Journal of Immunology. 2014 Sep 1;193(5):2512-2518. https://doi.org/10.4049/jimmunol.1400588
Feng, Dechun ; Wang, Yan ; Wang, Hua ; Weng, Honglei ; Kong, Xiaoni ; Martin-Murphy, Brittany V. ; Li, Yongmei ; Park, Ogyi ; Dooley, Steven ; Ju, Cynthia ; Gao, Bin. / Acute and chronic effects of IL-22 on acetaminophen-induced liver injury. In: Journal of Immunology. 2014 ; Vol. 193, No. 5. pp. 2512-2518.
@article{e44ae197368b4d4caede6e7f6aee3ead,
title = "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 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 wk resulted in a markedly increased susceptibility to AILI. Furthermore, the hepatic expression levels of cytochrome 2E1 (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 HNF-1α, 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 2 wk. 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 are also helpful to identify novel therapeutic targets for the treatment of AILI.",
author = "Dechun Feng and Yan Wang and Hua Wang and Honglei Weng and Xiaoni Kong and Martin-Murphy, {Brittany V.} and Yongmei Li and Ogyi Park and Steven Dooley and Cynthia Ju and Bin Gao",
year = "2014",
month = "9",
day = "1",
doi = "10.4049/jimmunol.1400588",
language = "English (US)",
volume = "193",
pages = "2512--2518",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "5",

}

TY - JOUR

T1 - Acute and chronic effects of IL-22 on acetaminophen-induced liver injury

AU - Feng, Dechun

AU - Wang, Yan

AU - Wang, Hua

AU - Weng, Honglei

AU - Kong, Xiaoni

AU - Martin-Murphy, Brittany V.

AU - Li, Yongmei

AU - Park, Ogyi

AU - Dooley, Steven

AU - Ju, Cynthia

AU - Gao, Bin

PY - 2014/9/1

Y1 - 2014/9/1

N2 - 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 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 wk resulted in a markedly increased susceptibility to AILI. Furthermore, the hepatic expression levels of cytochrome 2E1 (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 HNF-1α, 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 2 wk. 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 are also helpful to identify novel therapeutic targets for the treatment of AILI.

AB - 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 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 wk resulted in a markedly increased susceptibility to AILI. Furthermore, the hepatic expression levels of cytochrome 2E1 (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 HNF-1α, 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 2 wk. 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 are also helpful to identify novel therapeutic targets for the treatment of AILI.

UR - http://www.scopus.com/inward/record.url?scp=84907030420&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84907030420&partnerID=8YFLogxK

U2 - 10.4049/jimmunol.1400588

DO - 10.4049/jimmunol.1400588

M3 - Article

C2 - 25063867

AN - SCOPUS:84907030420

VL - 193

SP - 2512

EP - 2518

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 5

ER -