title: Soluble IgM links apoptosis to complement activation in early alcoholic liver disease in mice.
abstract: BACKGROUND
  Ethanol feeding in mice activates complement via C1q binding to apoptotic cells in the liver; complement contributes to ethanol-induced inflammation and injury. Despite the critical role of C1q in ethanol-induced injury, the mechanism by which ethanol activates C1q remains poorly understood. Secretory IgM (sIgM), traditionally considered to act as an anti-microbial, also has critical housekeeping functions, facilitating clearance of apoptotic cells, at least in part through activation of C1q. Therefore, we hypothesized that (1) ethanol-induced apoptosis in the liver recruits sIgM, facilitating the activation of C1q and complement and (2) C1INH (C1 esterase inhibitor), which inhibits C1 functional activity, prevents complement activation and decreases ethanol-induced liver injury.
  
  
  METHODS
  Female C57BL/6 wild-type, C1qa(-/-), BID(-/-) and sIgM(-/-) mice were fed ethanol containing liquid diets or pair-fed control diets. C1INH or vehicle was given via tail vein injection to ethanol- or pair-fed wild-type mice at 24 and 48h prior to euthanasia.
  
  
  RESULTS
  Ethanol exposure increased apoptosis in the liver, as well as the accumulation of IgM in the liver. In the early stages of ethanol feeding, C1q co-localized with IgM in the peri-sinusoidal space of the liver and accumulation of IgM and C3b was dependent on ethanol-induced BID-dependent apoptosis. sIgM(-/-) mice were protected from both ethanol-induced activation of complement and early ethanol-induced liver injury when compared to wild-type mice. Treatment with C1INH also decreased hepatic C3b deposition and ethanol-induced injury.
  
  
  CONCLUSIONS
  These data indicate that sIgM contributes to activation of complement and ethanol-induced increases in inflammatory cytokine expression and hepatocyte injury in the early stages of ethanol-induced liver injury.
authors.affiliation: Center for Liver Disease Research, Department of Pathobiology, Cleveland Clinic, United States.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Smathers
authors.affiliation: Center for Liver Disease Research, Department of Pathobiology, Cleveland Clinic, United States; Department of Gastroenterology, Cleveland Clinic, United States.
authors.forename: Dian J
authors.initials: DJ
authors.lastname: Chiang
authors.affiliation: Center for Liver Disease Research, Department of Pathobiology, Cleveland Clinic, United States.
authors.forename: Megan R
authors.initials: MR
authors.lastname: McMullen
authors.affiliation: Department of Pediatric Gastroenterology, University of California San Diego, San Diego, CA, United States.
authors.forename: Ariel E
authors.initials: AE
authors.lastname: Feldstein
authors.affiliation: Center for Liver Disease Research, Department of Pathobiology, Cleveland Clinic, United States.
authors.forename: Sanjoy
authors.initials: S
authors.lastname: Roychowdhury
authors.affiliation: Center for Liver Disease Research, Department of Pathobiology, Cleveland Clinic, United States; Department of Gastroenterology, Cleveland Clinic, United States; Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH, United States. Electronic address: nagyL3@ccf.org.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Nagy
mesh_terms: D000818:Animals; D017209:Apoptosis; D003167:Complement Activation; D003174:Complement C1 Inactivator Proteins / Q000494:pharmacology; D050718:Complement C1 Inhibitor Protein; D015922:Complement C1q / Q000037:antagonists & inhibitors / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D022781:Hepatocytes / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology*; D008108:Liver Diseases, Alcoholic / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D012995:Solubility
chemical_list: D003174:Complement C1 Inactivator Proteins; D050718:Complement C1 Inhibitor Protein; D016207:Cytokines; D007075:Immunoglobulin M; C469952:SERPING1 protein, human; C033027:secretory IgM; D015922:Complement C1q
keywords: Alcoholic liver disease; Apoptosis; Complement; Hepatocytes; Inflammation