Show simple item record

dc.contributor.authorPetrasek, Jan
dc.contributor.authorBala, Shashi
dc.contributor.authorCsak, Timea
dc.contributor.authorLippai, Dora
dc.contributor.authorKodys, Karen
dc.contributor.authorMenashy, Victoria
dc.contributor.authorBarrieau, Matthew
dc.contributor.authorMin, So-Yun
dc.contributor.authorKurt-Jones, Evelyn A.
dc.contributor.authorSzabo, Gyongyi
dc.date2022-08-11T08:08:36.000
dc.date.accessioned2022-08-23T16:01:06Z
dc.date.available2022-08-23T16:01:06Z
dc.date.issued2012-10-01
dc.date.submitted2012-10-10
dc.identifier.citation<p>J Clin Invest. 2012 Oct 1;122(10):3476-89. doi: 10.1172/JCI60777. <a href="http://dx.doi.org/10.1172/JCI60777" target="_blank">Link to article on publisher's site</a></p>
dc.identifier.issn0021-9738 (Linking)
dc.identifier.doi10.1172/JCI60777
dc.identifier.pmid22945633
dc.identifier.urihttp://hdl.handle.net/20.500.14038/31044
dc.description.abstractAlcoholic 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.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=22945633&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://dx.doi.org/10.1172/JCI60777
dc.rights<p>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.</p>
dc.subjectFatty Liver, Alcoholic
dc.subjectReceptors, Interleukin-1 Type I
dc.subjectInflammasones
dc.subjectDigestive System Diseases
dc.subjectGastroenterology
dc.subjectHepatology
dc.subjectImmunology and Infectious Disease
dc.titleIL-1 receptor antagonist ameliorates inflammasome-dependent alcoholic steatohepatitis in mice
dc.typeJournal Article
dc.source.journaltitleThe Journal of clinical investigation
dc.source.volume122
dc.source.issue10
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1100&amp;context=gastroenterology_pp&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/gastroenterology_pp/101
dc.identifier.contextkey3383599
refterms.dateFOA2022-08-23T16:01:07Z
html.description.abstract<p>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.</p>
dc.identifier.submissionpathgastroenterology_pp/101
dc.contributor.departmentDepartment of Medicine, Division of Infectious Diseases and Immunology
dc.contributor.departmentDepartment of Medicine, Division of Gastroenterology
dc.source.pages3476-89


Files in this item

Thumbnail
Name:
JCI60777.v3.pdf
Size:
9.042Mb
Format:
PDF

This item appears in the following Collection(s)

Show simple item record