title: IL-1 receptor antagonist ameliorates inflammasome-dependent alcoholic steatohepatitis in mice.
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.
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Petrasek
authors.forename: Shashi
authors.initials: S
authors.lastname: Bala
authors.forename: Timea
authors.initials: T
authors.lastname: Csak
authors.forename: Dora
authors.initials: D
authors.lastname: Lippai
authors.forename: Karen
authors.initials: K
authors.lastname: Kodys
authors.forename: Victoria
authors.initials: V
authors.lastname: Menashy
authors.forename: Matthew
authors.initials: M
authors.lastname: Barrieau
authors.forename: So-Yun
authors.initials: SY
authors.lastname: Min
authors.forename: Evelyn A
authors.initials: EA
authors.lastname: Kurt-Jones
authors.forename: Gyongyi
authors.initials: G
authors.lastname: Szabo
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D020170:Caspase 1 / Q000502:physiology; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics; D004353:Drug Evaluation, Preclinical; D000431:Ethanol / Q000633:toxicity; D005235:Fatty Liver, Alcoholic / Q000188:drug therapy* / Q000209:etiology; D005260:Female; D022781:Hepatocytes / Q000378:metabolism; D058847:Inflammasomes / Q000502:physiology*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000627:therapeutic use*; D053582:Interleukin-1alpha / Q000096:biosynthesis / Q000097:blood; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000097:blood / Q000502:physiology / Q000633:toxicity; D007728:Kupffer Cells / Q000473:pathology; D008103:Liver Cirrhosis / Q000209:etiology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D053573:Receptors, Interleukin-1 Type I / Q000172:deficiency / Q000502:physiology; D011994:Recombinant Proteins / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D002352:Carrier Proteins; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D058847:Inflammasomes; D053590:Interleukin 1 Receptor Antagonist Protein; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D053573:Receptors, Interleukin-1 Type I; D011994:Recombinant Proteins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D000431:Ethanol; D020170:Caspase 1