Department of Medicine, Division of Gastroenterology; Department of Medicine, Division of Infectious Diseases and Immunology
Fatty Liver, Alcoholic; Receptors, Interleukin-1 Type I; Inflammasones
Digestive System Diseases | Gastroenterology | Hepatology | Immunology and Infectious Disease
Alcoholic liver disease (ALD) is characterized by steatosis and upregulation of proinflammatory cytokines, including IL-1beta. IL-1beta, 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-1beta maturation is dependent on caspase-1 (Casp-1). Using IL-1Ra-treated mice as well as 3 mouse models deficient in regulators of IL-1beta activation (Casp-1 and ASC) or signaling (IL-1R1), we found that IL-1beta signaling is required for the development of alcohol-induced liver steatosis, inflammation, and injury. Increased IL-1beta 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-1beta 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-1beta 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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Copyright © 2012, American Society for Clinical Investigation. Publisher PDF posted as allowed by the publisher's author rights policy at http://static.the-jci.org/content_assets/admin/forms/jcicopyright.pdf.
DOI of Published Version
J Clin Invest. 2012 Oct 1;122(10):3476-89. doi: 10.1172/JCI60777. Link to article on publisher's site
The Journal of clinical investigation
Petrasek, Jan; Bala, Shashi; Csak, Timea; Lippai, Dora; Kodys, Karen; Menashy, Victoria; Barrieau, Matthew; Min, So-Yun; Kurt-Jones, Evelyn A.; and Szabo, Gyongyi, "IL-1 receptor antagonist ameliorates inflammasome-dependent alcoholic steatohepatitis in mice" (2012). Gastroenterology Publications and Presentations. 101.