1. Academic Validation
  2. IL-1 receptor antagonist ameliorates inflammasome-dependent alcoholic steatohepatitis in mice

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

  • J Clin Invest. 2012 Oct;122(10):3476-89. doi: 10.1172/JCI60777.
Jan Petrasek 1 Shashi Bala Timea Csak Dora Lippai Karen Kodys Victoria Menashy Matthew Barrieau So-Yun Min Evelyn A Kurt-Jones Gyongyi Szabo
Affiliations

Affiliation

  • 1 Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
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.

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