P-selectin suppresses hepatic inflammation and fibrosis in mice by regulating interferon γ and the IL-13 decoy receptor

Authors

  • Thomas A. Wynn,

    Corresponding author
    1. National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
    • Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bldg. 50, Rm. 6154, MSC 8003, Bethesda, MD 20892
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    • fax: 301-480-5025

  • Matthias Hesse,

    1. National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
    Current affiliation:
    1. College of Veterinary Medicine, Cornell University, Ithaca, NY
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  • Netanya G. Sandler,

    1. National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
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    • N.G.S. was a Howard Hughes Medical Institute-National Institutes of Health Research Scholar.

  • Mallika Kaviratne,

    1. National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
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  • Karl F. Hoffmann,

    1. National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
    Current affiliation:
    1. Department of Pathology, Microbiology and Parasitology Unit, University of Cambridge, Cambridge, UK
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  • Monica G. Chiaramonte,

    1. National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
    Current affiliation:
    1. Division of Immunobiology, The Children's Hospital Research Foundation, Cincinnati, OH
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  • Rachael Reiman,

    1. National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
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  • Allen W. Cheever,

    1. Biomedical Research Institute, Rockville, MD
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  • Joseph P. Sypek,

    1. Wyeth Research, Cambridge, MA
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  • Margaret M. Mentink-Kane

    1. National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
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Abstract

The selectin family of cell adhesion molecules is widely thought to promote inflammatory reactions by facilitating leukocyte recruitment. However, it was unexpectedly found that mice with targeted deletion of the P-selectin gene (PsKO mice) developed unpolarized type 1/type 2 cytokine responses and severely aggravated liver pathology following infection with the type 2–promoting pathogen Schistosoma mansoni. In fact, liver fibrosis, which is dependent on interleukin 13 (IL-13), increased by a factor of more than 6, despite simultaneous induction of the antifibrotic cytokine interferon gamma (IFN-γ). Inflammation, as measured by granuloma size, also increased significantly in the absence of P-selectin. When infected PsKO mice were treated with neutralizing anti-IFN-γ monoclonal antibodies, however, granuloma size was restored to wild-type levels; this finding revealed the potent proinflammatory role of IFN-γ when expressed concomitantly with IL-13. Untreated PsKO mice also exhibited a significant (sixfold) reduction in decoy IL-13 receptor (IL-13 receptor alpha-2) expression when compared with infected wild-type animals. It is noteworthy, however, that when decoy receptor activity was restored in PsKO mice by treatment with soluble IL-13 receptor alpha-2-Fc, the exacerbated fibrotic response was completely inhibited. Thus, reduced expression of the decoy IL-13 receptor mediated by the elevated type 1 cytokine response probably accounts for the enhanced activity of IL-13 in PsKO mice and for the resultant increase in collagen deposition. In conclusion, the current study has revealed the critical role of P-selectin in the progression of chronic liver disease caused by schistosome parasites. By suppressing IFN-γ and up-regulating the decoy IL-13 receptor, P-selectin dramatically inhibits the pathologic tissue remodeling that results from chronic type 2 cytokine–mediated inflammation. (HEPATOLOGY 2004;39:676–687.)

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