P-selectin suppresses hepatic inflammation and fibrosis in mice by regulating interferon gamma and the IL-13 decoy receptor.
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-gamma). 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-gamma monoclonal antibodies, however, granuloma size was restored to wild-type levels; this finding revealed the potent proinflammatory role of IFN-gamma 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-gamma 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.
National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 50, Room 6154, MSC 8003, Bethesda, MD 20892, USA. twynn@niaid.nih.gov
Thomas A
TA
Wynn
Matthias
M
Hesse
Netanya G
NG
Sandler
Mallika
M
Kaviratne
Karl F
KF
Hoffmann
Monica G
MG
Chiaramonte
Rachael
R
Reiman
Allen W
AW
Cheever
Joseph P
JP
Sypek
Margaret M
MM
Mentink-Kane
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002908:Chronic Disease; D016207:Cytokines / Q000378:metabolism; D004802:Eosinophilia / Q000473:pathology; D005260:Female; D015769:Granuloma, Respiratory Tract / Q000473:pathology; D006505:Hepatitis / Q000517:prevention & control*; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism*; D053661:Interleukin-13 Receptor alpha1 Subunit; D008103:Liver Cirrhosis / Q000473:pathology / Q000517:prevention & control*; D008171:Lung Diseases / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics; D019007:P-Selectin / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D018123:Receptors, Interleukin / Q000378:metabolism*; D053660:Receptors, Interleukin-13; D012552:Schistosomiasis / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D016207:Cytokines; C508183:Il13ra1 protein, mouse; D053661:Interleukin-13 Receptor alpha1 Subunit; D019007:P-Selectin; D020033:Protein Isoforms; D018123:Receptors, Interleukin; D053660:Receptors, Interleukin-13; D007371:Interferon-gamma