title: Complement and alcoholic liver disease: role of C1q in the pathogenesis of ethanol-induced liver injury in mice.
abstract: OBJECTIVE
  Complement is involved in the development of alcoholic liver disease in mice; however, the mechanisms for complement activation during ethanol exposure have not been identified. C1q, the recognition subunit of the first complement component, binds to apoptotic cells, thereby activating the classical complement pathway. Because ethanol exposure increases hepatocellular apoptosis, we hypothesized that ethanol-induced apoptosis would lead to activation of complement via the classical pathway.
  
  
  METHODS
  Wild-type and C1qa-/- mice were allowed free access to ethanol-containing diets or pair-fed control diets for 4 or 25 days.
  
  
  RESULTS
  Ethanol feeding for 4 days increased apoptosis of Kupffer cells in both wild-type and C1qa-/- mice. Ethanol-induced deposition of C1q and C3b/iC3b/C3c was colocalized with apoptotic Kupffer cells in wild-type, but not C1qa-/-, mice. Furthermore, ethanol-induced increases in tumor necrosis factor-alpha and interleukin-6 expression at this early time point were suppressed in C1q-deficient mice. Chronic ethanol feeding (25 days) increased steatosis, hepatocyte apoptosis, and activity of serum alanine and aspartate aminotransferases in wild-type mice. These markers of hepatocyte injury were attenuated in C1qa-/- mice. In contrast, chronic ethanol (25 days)-induced increases in cytochrome P450 2E1 expression and oxidative stress did not differ between wild-type and C1qa-/- mice.
  
  
  CONCLUSIONS
  For the first time, these data indicate that ethanol activates the classical complement pathway via C1q binding to apoptotic cells in the liver and that C1q contributes to the pathogenesis of ethanol-induced liver injury.
authors.affiliation: Department of Nutrition, Case Western Reserve University, Cleveland, Ohio 44195, USA.
authors.forename: Jessica I
authors.initials: JI
authors.lastname: Cohen
authors.forename: Sanjoy
authors.initials: S
authors.lastname: Roychowdhury
authors.forename: Megan R
authors.initials: MR
authors.lastname: McMullen
authors.forename: Abram B
authors.initials: AB
authors.lastname: Stavitsky
authors.forename: Laura E
authors.initials: LE
authors.lastname: Nagy
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000428:Alcohol Drinking / Q000009:adverse effects*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001219:Aspartate Aminotransferases / Q000097:blood; D003167:Complement Activation / Q000187:drug effects*; D015922:Complement C1q / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D003179:Complement C3b / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004790:Enzyme Induction; D000431:Ethanol / Q000633:toxicity*; D005234:Fatty Liver / Q000139:chemically induced / Q000276:immunology; D005260:Female; D018836:Inflammation Mediators / Q000378:metabolism; D007728:Kupffer Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013997:Time Factors
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D000431:Ethanol; D015922:Complement C1q; D003179:Complement C3b; D019392:Cytochrome P-450 CYP2E1; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase