IL-1 receptor antagonist ameliorates inflammasome-dependent alcoholic steatohepatitis in mice

Jan Petrasek, Shashi Bala, Timea Csak, Dora Lippai, Karen Kodys, Victoria Menashy, Matthew Barrieau, So Yun Min, Evelyn A. Kurt-Jones, Gyongyi Szabo

Research output: Contribution to journalArticle

341 Citations (Scopus)

Abstract

Alcoholic liver disease (ALD) is characterized by steatosis and upregulation of proinflammatory cytokines, including IL-1β. IL-1β, type I IL-1 receptor (IL-1R1), and IL-1 receptor antagonist (IL-1Ra) are all important regulators of the IL-1 signaling complex, which plays a role in inflammation. Furthermore, IL-1β maturation is dependent on caspase-1 (Casp-1). Using IL-1Ra-treated mice as well as 3 mouse models deficient in regulators of IL-1β activation (Casp-1 and ASC) or signaling (IL-1R1), we found that IL-1β signaling is required for the development of alcohol-induced liver steatosis, inflammation, and injury. Increased IL-1β was due to upregulation of Casp-1 activity and inflammasome activation. The pathogenic role of IL-1 signaling in ALD was attributable to the activation of the inflammasome in BM-derived Kupffer cells. Importantly, in vivo intervention with a recombinant IL-1Ra blocked IL-1 signaling and markedly attenuated alcohol-induced liver inflammation, steatosis, and damage. Furthermore, physiological doses of IL-1β induced steatosis, increased the inflammatory and prosteatotic chemokine MCP-1 in hepatocytes, and augmented TLR4-dependent upregulation of inflammatory signaling in macrophages. In conclusion, we demonstrated that Casp-1-dependent upregulation of IL-1β and signaling mediated by IL-1R1 are crucial in ALD pathogenesis. Our findings suggest a potential role of IL-1R1 inhibition in the treatment of ALD.

Original languageEnglish
Pages (from-to)3476-3489
Number of pages14
JournalJournal of Clinical Investigation
Volume122
Issue number10
DOIs
Publication statusPublished - Oct 1 2012

ASJC Scopus subject areas

  • Medicine(all)

Fingerprint Dive into the research topics of 'IL-1 receptor antagonist ameliorates inflammasome-dependent alcoholic steatohepatitis in mice'. Together they form a unique fingerprint.

  • Cite this

    Petrasek, J., Bala, S., Csak, T., Lippai, D., Kodys, K., Menashy, V., Barrieau, M., Min, S. Y., Kurt-Jones, E. A., & Szabo, G. (2012). IL-1 receptor antagonist ameliorates inflammasome-dependent alcoholic steatohepatitis in mice. Journal of Clinical Investigation, 122(10), 3476-3489. https://doi.org/10.1172/JCI60777