title: Protective role of macrophage-derived ceruloplasmin in inflammatory bowel disease.
abstract: OBJECTIVE
  Intestinal microflora and inflammatory cell infiltrates play critical roles in the pathogenesis of acute colitis. Ceruloplasmin is an acute-phase plasma protein produced by hepatocytes and activated macrophages, and has ferroxidase with bactericidal activities. The goal is to understand the role of ceruloplasmin in colitis progression in a genetically modified murine model.
  
  
  METHODS
  Experimental colitis was induced in ceruloplasmin null (Cp(-/-)) and wild-type (WT) mice by dextran sulphate sodium administration. The role of ceruloplasmin was further evaluated by transplantation of WT macrophages into Cp(-/-) mice.
  
  
  RESULTS
  Cp(-/-) mice rapidly lost weight and were moribund by day 14, while WT mice survived at least 30 days. Colon culture supernatants from Cp(-/-) mice exhibited elevated levels of TNFα, KC and MCP-1, indicative of increased inflammation and neutrophil and macrophage infiltration. Elevated leucocytes and severe histopathology were observed in Cp(-/-) mice. Elevated protein carbonyl content was detected in colons from Cp(-/-) mice suggesting ceruloplasmin antioxidant activity might contribute to its protective function. Unexpectedly, intraperitoneal administration of human ceruloplasmin into Cp(-/-) mice did not afford protection. Bone marrow transplantation from WT mice or injection of isolated peripheral blood monocytes markedly reduced severity of colitis and morbidity in Cp(-/-) mice.
  
  
  CONCLUSIONS
  Macrophage-derived ceruloplasmin contributes importantly to protection against inflammation and tissue injury in acute and chronic experimental colitis. The findings suggest that defects in ceruloplasmin expression or processing may influence the onset or progression of inflammatory bowel disease in patients.
authors.affiliation: Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Bakytzhan
authors.initials: B
authors.lastname: Bakhautdin
authors.forename: Maria
authors.initials: M
authors.lastname: Febbraio
authors.forename: Esen
authors.initials: E
authors.lastname: Goksoy
authors.forename: Carol A
authors.initials: CA
authors.lastname: de la Motte
authors.forename: Muhammet F
authors.initials: MF
authors.lastname: Gulen
authors.forename: Erin Patricia
authors.initials: EP
authors.lastname: Childers
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Hazen
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Li
authors.forename: Paul L
authors.initials: PL
authors.lastname: Fox
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D002570:Ceruloplasmin / Q000502:physiology*; D018925:Chemokines / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D017931:DNA Primers / Q000737:chemistry; D016264:Dextran Sulfate; D018450:Disease Progression; D005260:Female; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D050050:Protein Carbonylation; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D018925:Chemokines; D017931:DNA Primers; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D016264:Dextran Sulfate; D002570:Ceruloplasmin