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Protective role of macrophage-derived ceruloplasmin in inflammatory bowel disease
  1. Bakytzhan Bakhautdin1,2,
  2. Maria Febbraio3,
  3. Esen Goksoy1,
  4. Carol A de la Motte4,
  5. Muhammet F Gulen5,
  6. Erin Patricia Childers1,
  7. Stanley L Hazen1,
  8. Xiaoxia Li5,
  9. Paul L Fox1
  1. 1Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
  2. 2Department of Biological Sciences, Cleveland State University, Cleveland, Ohio, USA
  3. 3Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
  4. 4Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
  5. 5Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
  1. Correspondence to Dr Paul L Fox, Department of Cell Biology, Lerner Research Institute, 9500 Euclid Avenue/NC10, Cleveland Clinic, Cleveland, OH 44195, USA; foxp{at}ccf.org

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.

Design 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.

Conclusion 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.

  • Basic sciences
  • cell migration
  • ceruloplasmin
  • colonic diseases
  • experimental colitis
  • inflammatory diseases
  • lipids
  • macrophage
  • molecular biology
  • transplantation

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Footnotes

  • Funding Supported by National Institutes of Health grants P01 HL029582 (to PLF and XL), P01 HL076491 (to PLF and SLH) and R01 DK083359 (to PLF).

  • Competing interests None.

  • Ethics approval All in-vivo mouse experiments followed a protocol approved by Cleveland Clinic Animal Review Committee. De-identified samples of redundant human colon were collected at the time of surgical resection according to a Cleveland Clinic Institutional Review Board-approved protocol.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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