title: Lack of interleukin-1α or interleukin-1β inhibits transformation of steatosis to steatohepatitis and liver fibrosis in hypercholesterolemic mice.
abstract: OBJECTIVE
  The identification of the cellular and molecular pathways that mediate the development of non-alcoholic steatohepatitis is of crucial importance. Cytokines produced by liver-resident and infiltrating inflammatory cells, play a pivotal role in liver inflammation. The role of the proinflammatory cytokines IL-1α and IL-1β in steatohepatitis remains elusive.
  
  
  METHODS
  We employed IL-1α and IL-1β-deficient mice and transplanted marrow cells to study the role of liver-resident and bone marrow-derived IL-1 in steatosis and its progression to steatohepatitis.
  
  
  RESULTS
  Atherogenic diet-induced steatohepatitis in wild-type mice was associated with 16 and 4.6 fold-elevations in mRNA levels of hepatic IL-1α and IL-1β, respectively. In mice deficient in either IL-1α or IL-1β the transformation of steatosis to steatohepatitis and liver fibrosis was markedly reduced. This protective effect in IL-1α-deficient mice was noted despite increased liver cholesterol levels. Deficiency of IL-1α markedly reduced plasma serum amyloid A and steady-state levels of mRNA coding for inflammatory genes (P-selectin, CXCL1, IL-6, and TNFα) as well as pro-fibrotic genes (MMP-9 and Collagen) and particularly a 50% decrease in TGFβ levels (p = 0.004). IL-1α mRNA levels were two-folds lower in IL-1β-deficient mice, and IL-1β transcripts were three-folds lower in IL-1α-deficient compared to wild-type mice. Hepatic cell derived IL-1α rather than from recruited bone marrow-derived cells was required for steatohepatitis development.
  
  
  CONCLUSIONS
  These data demonstrate the critical role of IL-1α and IL-1β in the transformation of steatosis to steatohepatitis and liver fibrosis in hypercholesterolemic mice. Therefore, the potential of neutralizing IL-1α and/or IL-1β to inhibit the development of steatohepatitis should be explored.
authors.affiliation: The Bert W. Strassburger Lipid Center, Sheba Medical Center, Tel Hashomer, Israel. yehuda.kamari@sheba.health.gov.il
authors.forename: Yehuda
authors.initials: Y
authors.lastname: Kamari
authors.forename: Aviv
authors.initials: A
authors.lastname: Shaish
authors.forename: Einav
authors.initials: E
authors.lastname: Vax
authors.forename: Shay
authors.initials: S
authors.lastname: Shemesh
authors.forename: Michal
authors.initials: M
authors.lastname: Kandel-Kfir
authors.forename: Yaron
authors.initials: Y
authors.lastname: Arbel
authors.forename: Sarita
authors.initials: S
authors.lastname: Olteanu
authors.forename: Iris
authors.initials: I
authors.lastname: Barshack
authors.forename: Shahar
authors.initials: S
authors.lastname: Dotan
authors.forename: Elana
authors.initials: E
authors.lastname: Voronov
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.forename: Ron N
authors.initials: RN
authors.lastname: Apte
authors.forename: Dror
authors.initials: D
authors.lastname: Harats
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D054360:Chemokine CXCL1 / Q000235:genetics / Q000378:metabolism; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D004036:Diet, Atherogenic; D018450:Disease Progression; D005234:Fatty Liver / Q000378:metabolism* / Q000473:pathology; D015870:Gene Expression; D006505:Hepatitis / Q000378:metabolism* / Q000473:pathology; D006937:Hypercholesterolemia / Q000150:complications; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism; D053582:Interleukin-1alpha / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019007:P-Selectin / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D000685:Serum Amyloid A Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D054360:Chemokine CXCL1; D007375:Interleukin-1; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D019007:P-Selectin; D012333:RNA, Messenger; D000685:Serum Amyloid A Protein; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen; D020780:Matrix Metalloproteinase 9