P-Selectin Suppresses Hepatic Inflammation and Fibrosis in Mice by Regulating Interferon γ and the IL-13 Decoy Receptor

Thomas A. Wynn, Matthias Hesse, Netanya G. Sandler, Mallika Kaviratne, Karl F. Hoffmann, Monica G. Chiaramonte, Rachael Reiman, Allen W. Cheever, Joseph P. Sypek, Margaret M. Mentink-Kane

Research output: Contribution to journalArticle

28 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)676-687
Number of pages12
JournalHepatology
Volume39
Issue number3
DOIs
StatePublished - Mar 2004
Externally publishedYes

Fingerprint

Interleukin-13 Receptor alpha2 Subunit
P-Selectin
Interferons
Fibrosis
Inflammation
Interferon-gamma
Interleukin-13
Liver
Interleukin-13 Receptors
Cytokines
Granuloma
Selectins
Wild Animals
Schistosoma mansoni
Cell Adhesion Molecules
Liver Cirrhosis
Liver Diseases
Parasites
Leukocytes
Chronic Disease

ASJC Scopus subject areas

  • Hepatology

Cite this

Wynn, T. A., Hesse, M., Sandler, N. G., Kaviratne, M., Hoffmann, K. F., Chiaramonte, M. G., ... Mentink-Kane, M. M. (2004). P-Selectin Suppresses Hepatic Inflammation and Fibrosis in Mice by Regulating Interferon γ and the IL-13 Decoy Receptor. Hepatology, 39(3), 676-687. https://doi.org/10.1002/hep.20102

P-Selectin Suppresses Hepatic Inflammation and Fibrosis in Mice by Regulating Interferon γ and the IL-13 Decoy Receptor. / Wynn, Thomas A.; Hesse, Matthias; Sandler, Netanya G.; Kaviratne, Mallika; Hoffmann, Karl F.; Chiaramonte, Monica G.; Reiman, Rachael; Cheever, Allen W.; Sypek, Joseph P.; Mentink-Kane, Margaret M.

In: Hepatology, Vol. 39, No. 3, 03.2004, p. 676-687.

Research output: Contribution to journalArticle

Wynn, TA, Hesse, M, Sandler, NG, Kaviratne, M, Hoffmann, KF, Chiaramonte, MG, Reiman, R, Cheever, AW, Sypek, JP & Mentink-Kane, MM 2004, 'P-Selectin Suppresses Hepatic Inflammation and Fibrosis in Mice by Regulating Interferon γ and the IL-13 Decoy Receptor', Hepatology, vol. 39, no. 3, pp. 676-687. https://doi.org/10.1002/hep.20102
Wynn, Thomas A. ; Hesse, Matthias ; Sandler, Netanya G. ; Kaviratne, Mallika ; Hoffmann, Karl F. ; Chiaramonte, Monica G. ; Reiman, Rachael ; Cheever, Allen W. ; Sypek, Joseph P. ; Mentink-Kane, Margaret M. / P-Selectin Suppresses Hepatic Inflammation and Fibrosis in Mice by Regulating Interferon γ and the IL-13 Decoy Receptor. In: Hepatology. 2004 ; Vol. 39, No. 3. pp. 676-687.
@article{d475b4b7bb0d407cba060dc5c02c248e,
title = "P-Selectin Suppresses Hepatic Inflammation and Fibrosis in Mice by Regulating Interferon γ and the IL-13 Decoy Receptor",
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.",
author = "Wynn, {Thomas A.} and Matthias Hesse and Sandler, {Netanya G.} and Mallika Kaviratne and Hoffmann, {Karl F.} and Chiaramonte, {Monica G.} and Rachael Reiman and Cheever, {Allen W.} and Sypek, {Joseph P.} and Mentink-Kane, {Margaret M.}",
year = "2004",
month = "3",
doi = "10.1002/hep.20102",
language = "English (US)",
volume = "39",
pages = "676--687",
journal = "Hepatology",
issn = "0270-9139",
publisher = "John Wiley and Sons Ltd",
number = "3",

}

TY - JOUR

T1 - P-Selectin Suppresses Hepatic Inflammation and Fibrosis in Mice by Regulating Interferon γ and the IL-13 Decoy Receptor

AU - Wynn, Thomas A.

AU - Hesse, Matthias

AU - Sandler, Netanya G.

AU - Kaviratne, Mallika

AU - Hoffmann, Karl F.

AU - Chiaramonte, Monica G.

AU - Reiman, Rachael

AU - Cheever, Allen W.

AU - Sypek, Joseph P.

AU - Mentink-Kane, Margaret M.

PY - 2004/3

Y1 - 2004/3

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=12144290869&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=12144290869&partnerID=8YFLogxK

U2 - 10.1002/hep.20102

DO - 10.1002/hep.20102

M3 - Article

VL - 39

SP - 676

EP - 687

JO - Hepatology

JF - Hepatology

SN - 0270-9139

IS - 3

ER -