{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T22:11:25Z","timestamp":1790892685370,"version":"4.1.0"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":4201,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2004,3]]},"abstract":"<jats:sec>\n            <jats:title\/>\n            <jats:p>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 <jats:italic toggle=\"yes\">Schistosoma mansoni<\/jats:italic>. 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-\u03b3). 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-\u03b3 monoclonal antibodies, however, granuloma size was restored to wild-type levels; this finding revealed the potent proinflammatory role of IFN-\u03b3 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-\u03b3 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.)<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.20102","type":"journal-article","created":{"date-parts":[[2004,3,1]],"date-time":"2004-03-01T08:02:00Z","timestamp":1078128120000},"page":"676-687","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":29,"title":["P-selectin suppresses hepatic inflammation and fibrosis in mice by regulating interferon \u03b3 and the IL-13 decoy receptor"],"prefix":"10.1097","volume":"39","author":[{"given":"Thomas A.","family":"Wynn","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Hesse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Netanya G.","family":"Sandler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mallika","family":"Kaviratne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl F.","family":"Hoffmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica G.","family":"Chiaramonte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachael","family":"Reiman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allen W.","family":"Cheever","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph P.","family":"Sypek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret M.","family":"Mentink-Kane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"R1-15-20241201","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1146\/annurev.immunol.21.120601.141142","article-title":"IL-13 effector functions.","volume":"21","author":"Wynn","year":"2003","journal-title":"Annu Rev Immunol"},{"key":"R2-15-20241201","doi-asserted-by":"crossref","first-page":"6406","DOI":"10.4049\/jimmunol.164.12.6406","article-title":"IL-10 and the dangers of immune polarization: excessive type 1 and type 2 cytokine responses induce distinct forms of lethal immunopathology in murine schistosomiasis.","volume":"164","author":"Hoffmann","year":"2000","journal-title":"J Immunol"},{"key":"R3-15-20241201","doi-asserted-by":"crossref","first-page":"2545","DOI":"10.1096\/fj.01-0306fje","article-title":"Disease fingerprinting with cDNA microarrays reveals distinct gene expression profiles in lethal type 1 and type 2 cytokine-mediated inflammatory reactions.","volume":"15","author":"Hoffmann","year":"2001","journal-title":"FASEB J"},{"key":"R4-15-20241201","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1172\/JCI7325","article-title":"An IL-13 inhibitor blocks the development of hepatic fibrosis during a T-helper type 2-dominated inflammatory response.","volume":"104","author":"Chiaramonte","year":"1999","journal-title":"J Clin Invest"},{"key":"R5-15-20241201","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1053\/jhep.2001.26376","article-title":"Studies of murine schistosomiasis reveal interleukin-13 blockade as a treatment for established and progressive liver fibrosis.","volume":"34","author":"Chiaramonte","year":"2001","journal-title":"HEPATOLOGY"},{"key":"R6-15-20241201","doi-asserted-by":"crossref","first-page":"2585","DOI":"10.4049\/jimmunol.164.5.2585","article-title":"Schistosome infection of transgenic mice defines distinct and contrasting pathogenic roles for IL-4 and IL-13: IL-13 is a profibrotic agent.","volume":"164","author":"Fallon","year":"2000","journal-title":"J Immunol"},{"key":"R7-15-20241201","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1038\/376594a0","article-title":"An IL-12-based vaccination method for preventing fibrosis induced by schistosome infection.","volume":"376","author":"Wynn","year":"1995","journal-title":"Nature"},{"key":"R8-15-20241201","doi-asserted-by":"crossref","first-page":"1850","DOI":"10.4049\/jimmunol.160.4.1850","article-title":"Th2 cells are required for the Schistosoma mansoni egg-induced granulomatous response.","volume":"160","author":"Kaplan","year":"1998","journal-title":"J Immunol"},{"key":"R9-15-20241201","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1093\/intimm\/8.4.435","article-title":"Schistosoma mansoni in IL-4-deficient mice.","volume":"8","author":"Pearce","year":"1996","journal-title":"Int Immunol"},{"key":"R10-15-20241201","doi-asserted-by":"crossref","first-page":"337","DOI":"10.4049\/jimmunol.163.1.337","article-title":"Schistosome-infected IL-4 receptor knockout (KO) mice, in contrast to IL-4 KO mice, fail to develop granulomatous pathology while maintaining the same lymphokine expression profile.","volume":"163","author":"Jankovic","year":"1999","journal-title":"J Immunol"},{"key":"R11-15-20241201","doi-asserted-by":"crossref","first-page":"3259","DOI":"10.1182\/blood.V88.9.3259.bloodjournal8893259","article-title":"Selectins and their ligands: current concepts and controversies.","volume":"88","author":"Kansas","year":"1996","journal-title":"Blood"},{"key":"R12-15-20241201","doi-asserted-by":"crossref","first-page":"214","DOI":"10.7861\/clinmedicine.1-3-214","article-title":"Eosinophil trafficking in asthma.","volume":"1","author":"Wardlaw","year":"2001","journal-title":"Clin Med"},{"key":"R13-15-20241201","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1111\/j.1749-6632.2001.tb03706.x","article-title":"Human endothelial cell presentation of antigen and the homing of memoryeffector T cells to skin.","volume":"941","author":"Pober","year":"2001","journal-title":"Ann N Y Acad Sci"},{"key":"R14-15-20241201","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1385\/IR:22:2-3:299","article-title":"Adhesion molecule cascades direct lymphocyte recirculation and leukocyte migration during inflammation.","volume":"22","author":"Steeber","year":"2000","journal-title":"Immunol Res"},{"key":"R15-15-20241201","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1038\/385081a0","article-title":"P- and E-selectin mediate recruitment of T-helper-1 but not T-helper-2 cells into inflammed sic tissues.","volume":"385","author":"Austrup","year":"1997","journal-title":"Nature"},{"key":"R16-15-20241201","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1084\/jem.185.3.573","article-title":"P-selectin glycoprotein ligand-1 (PSGL-1) on T helper 1 but not on T helper 2 cells binds to P-selectin and supports migration into inflamed skin.","volume":"185","author":"Borges","year":"1997","journal-title":"J Exp Med"},{"key":"R17-15-20241201","doi-asserted-by":"crossref","first-page":"753","DOI":"10.4049\/jimmunol.153.2.753","article-title":"Anti-IL-4 treatment of Schistosoma mansoni-infected mice inhibits development of T cells and non-B, non-T cells expressing Th2 cytokines while decreasing egg-induced hepatic fibrosis.","volume":"153","author":"Cheever","year":"1994","journal-title":"J Immunol"},{"key":"R18-15-20241201","doi-asserted-by":"crossref","first-page":"2317","DOI":"10.4049\/jimmunol.161.5.2317","article-title":"The murine IL-13 receptor alpha 2: molecular cloning, characterization, and comparison with murine IL-13 receptor alpha 1.","volume":"161","author":"Donaldson","year":"1998","journal-title":"J Immunol"},{"key":"R19-15-20241201","doi-asserted-by":"crossref","first-page":"6533","DOI":"10.4049\/jimmunol.167.11.6533","article-title":"Differential regulation of nitric oxide synthase-2 and arginase-1 by type 1type 2 cytokines in vivo: granulomatous pathology is shaped by the pattern of L-arginine metabolism.","volume":"167","author":"Hesse","year":"2001","journal-title":"J Immunol"},{"key":"R20-15-20241201","doi-asserted-by":"crossref","first-page":"1551","DOI":"10.1084\/jem.179.5.1551","article-title":"Endogenous interleukin 12 (IL-12) regulates granuloma formation induced by eggs of Schistosoma mansoni and exogenous IL-12 both inhibits and prophylactically immunizes against egg pathology.","volume":"179","author":"Wynn","year":"1994","journal-title":"J Exp Med"},{"key":"R21-15-20241201","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/1074-7613(94)90076-0","article-title":"Lymphocyte homing and leukocyte rolling and migration are impaired in L-selectin-deficient mice.","volume":"1","author":"Arbones","year":"1994","journal-title":"Immunity"},{"key":"R22-15-20241201","doi-asserted-by":"crossref","first-page":"2673","DOI":"10.1182\/blood.V97.9.2673","article-title":"The interleukin-13 receptor alpha2 chain: an essential component for binding and internalization but not for interleukin-13-induced signal transduction through the STAT6 pathway.","volume":"97","author":"Kawakami","year":"2001","journal-title":"Blood"},{"key":"R23-15-20241201","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1084\/jem.20020906","article-title":"Enhanced interleukin (IL)-13 responses in mice lacking IL-13 receptor alpha 2.","volume":"197","author":"Wood","year":"2003","journal-title":"J Exp Med"},{"key":"R24-15-20241201","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1084\/jem.20020903","article-title":"Regulation and function of the interleukin 13 receptor alpha 2 during a T helper cell type 2-dominant immune response.","volume":"197","author":"Chiaramonte","year":"2003","journal-title":"J Exp Med"},{"key":"R25-15-20241201","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1084\/jem.180.1.371","article-title":"Eosinophil adhesion to nasal polyp endothelium is P-selectin-dependent.","volume":"180","author":"Symon","year":"1994","journal-title":"J Exp Med"},{"key":"R26-15-20241201","doi-asserted-by":"crossref","first-page":"3929","DOI":"10.4049\/jimmunol.159.8.3929","article-title":"P-selectin, L-selectin, and alpha 4 integrin have distinct roles in eosinophil tethering and arrest on vascular endothelial cells under physiological flow conditions.","volume":"159","author":"Kitayama","year":"1997","journal-title":"J Immunol"},{"key":"R27-15-20241201","doi-asserted-by":"crossref","first-page":"2847","DOI":"10.1182\/blood.V91.8.2847.2847_2847_2856","article-title":"Inhibition of eosinophil rolling and recruitment in P-selectin- and intracellular adhesion molecule-1-deficient mice.","volume":"91","author":"Broide","year":"1998","journal-title":"Blood"},{"key":"R28-15-20241201","doi-asserted-by":"crossref","first-page":"11452","DOI":"10.1073\/pnas.96.20.11452","article-title":"Multiple, targeted deficiencies in selectins reveal a predominant role for P-selectin in leukocyte recruitment.","volume":"96","author":"Robinson","year":"1999","journal-title":"Proc Natl Acad Sci U S A"},{"key":"R29-15-20241201","doi-asserted-by":"crossref","first-page":"3146","DOI":"10.1182\/blood.V95.10.3146","article-title":"Interleukin-13 induces PSGL-1P-selectin-dependent adhesion of eosinophils, but not neutrophils, to human umbilical vein endothelial cells under flow.","volume":"95","author":"Woltmann","year":"2000","journal-title":"Blood"},{"key":"R30-15-20241201","doi-asserted-by":"crossref","first-page":"5297","DOI":"10.1182\/blood.V87.12.5297.bloodjournal87125297","article-title":"Selectins mediate eosinophil recruitment in vivo: a comparison with their role in neutrophil influx.","volume":"87","author":"Henriques","year":"1996","journal-title":"Blood"},{"key":"R31-15-20241201","first-page":"1336","article-title":"Soluble P-selectin glycoprotein ligand 1 inhibits ocular inflammation in a murine model of allergy.","volume":"40","author":"Strauss","year":"1999","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"R32-15-20241201","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1016\/S0091-6749(99)70069-2","article-title":"Molecular basis for selective eosinophil trafficking in asthma: a multistep paradigm.","volume":"104","author":"Wardlaw","year":"1999","journal-title":"J Allergy Clin Immunol"},{"key":"R33-15-20241201","first-page":"3856","article-title":"Impaired eosinophil recruitment to the cornea in P-selectin-deficient mice in Onchocerca volvulus keratitis (River blindness).","volume":"41","author":"Kaifi","year":"2000","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"R34-15-20241201","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1165\/ajrcmb.18.2.2829","article-title":"Inhibition of pulmonary eosinophilia in P-selectin- and ICAM-1-deficient mice.","volume":"18","author":"Broide","year":"1998","journal-title":"Am J Respir Cell Mol Biol"},{"key":"R35-15-20241201","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1002\/eji.1830270607","article-title":"P-selectin glycoprotein ligand-1 mediates rolling of mouse bone marrow-derived mast cells on P-selectin but not efficiently on E-selectin.","volume":"27","author":"Steegmaier","year":"1997","journal-title":"Eur J Immunol"},{"key":"R36-15-20241201","doi-asserted-by":"crossref","first-page":"1871","DOI":"10.1084\/jem.184.5.1871","article-title":"Schistosoma mansoni egg-induced early IL-4 production is dependent upon IL-5 and eosinophils.","volume":"184","author":"Sabin","year":"1996","journal-title":"J Exp Med"},{"key":"R37-15-20241201","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1159\/000235226","article-title":"Importance of mast-cell derived eosinophil chemotactic factor A on granuloma formation in murine Schistosomiasis japonica: evaluation using mast-cell-deficient WWV mice.","volume":"92","author":"Owhashi","year":"1990","journal-title":"Int Arch Allergy Appl Immunol"},{"key":"R38-15-20241201","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1016\/0035-9203(67)90125-3","article-title":"Pathological lesions associated with Schistosoma mansoni infection in man.","volume":"61","author":"Cheever","year":"1967","journal-title":"Trans R Soc Trop Med Hyg"},{"key":"R39-15-20241201","doi-asserted-by":"crossref","first-page":"920","DOI":"10.4049\/jimmunol.162.2.920","article-title":"IL-13 is a key regulatory cytokine for Th2 cell-mediated pulmonary granuloma formation and IgE responses induced by Schistosoma mansoni eggs.","volume":"162","author":"Chiaramonte","year":"1999","journal-title":"J Immunol"},{"key":"R40-15-20241201","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1006\/cyto.1999.0595","article-title":"Interleukin 4 and 13 participation in mycobacterial (type-1) and schistosomal (type-2) antigen-elicited pulmonary granuloma formation: multiparameter analysis of cellular recruitment, chemokine expression and cytokine networks.","volume":"12","author":"Ruth","year":"2000","journal-title":"Cytokine"},{"key":"R41-15-20241201","doi-asserted-by":"crossref","first-page":"1939","DOI":"10.1084\/jem.189.12.1939","article-title":"Interleukin 13 is secreted by and stimulates the growth of Hodgkin and Reed-Sternberg cells.","volume":"189","author":"Kapp","year":"1999","journal-title":"J Exp Med"},{"key":"R42-15-20241201","doi-asserted-by":"crossref","first-page":"2258","DOI":"10.1126\/science.282.5397.2258","article-title":"Interleukin-13: central mediator of allergic asthma. see comments.","volume":"282","author":"Wills-Karp","year":"1998","journal-title":"Science"},{"key":"R43-15-20241201","doi-asserted-by":"crossref","first-page":"2261","DOI":"10.1126\/science.282.5397.2261","article-title":"Requirement for IL-13 independently of IL-4 in experimental asthma.","volume":"282","author":"Grunig","year":"1998","journal-title":"Science"},{"key":"R44-15-20241201","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1172\/JCI5155","article-title":"Allergen-specific Th1 cells fail to counterbalance Th2 cell-induced airway hyperreactivity but cause severe airway inflammation.","volume":"103","author":"Hansen","year":"1999","journal-title":"J Clin Invest"},{"key":"R45-15-20241201","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1172\/JCI7631","article-title":"Cooperation between Th1 and Th2 cells in a murine model of eosinophilic airway inflammation.","volume":"104","author":"Randolph","year":"1999","journal-title":"J Clin Invest"},{"key":"R46-15-20241201","doi-asserted-by":"crossref","first-page":"1769","DOI":"10.4049\/jimmunol.167.3.1769","article-title":"IL-13 and IFN-gamma: interactions in lung inflammation.","volume":"167","author":"Ford","year":"2001","journal-title":"J Immunol"},{"key":"R47-15-20241201","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1165\/ajrcmb.22.2.f174","article-title":"Could asthma be worsened by stimulating the T-helper type 1 immune response?","volume":"22","author":"Castro","year":"2000","journal-title":"Am J Respir Cell Mol Biol"},{"key":"R48-15-20241201","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1002\/hep.1840100508","article-title":"Gamma-interferon treatment inhibits collagen deposition in murine schistosomiasis.","volume":"10","author":"Czaja","year":"1993","journal-title":"Hepatology"},{"key":"R49-15-20241201","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1172\/JCI5183","article-title":"P-selectin deficiency exacerbates experimental glomerulonephritis: a protective role for endothelial P-selectin in inflammation.","volume":"103","author":"Rosenkranz","year":"1999","journal-title":"J Clin Invest"},{"key":"R50-15-20241201","doi-asserted-by":"crossref","first-page":"2844","DOI":"10.4049\/jimmunol.163.5.2844","article-title":"Acceleration and increased severity of collagen-induced arthritis in P-selectin mutant mice.","volume":"163","author":"Bullard","year":"1999","journal-title":"J Immunol"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.20102","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-200403000-00015","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,1]],"date-time":"2024-12-01T12:02:51Z","timestamp":1733054571000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-200403000-00015"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2004,3]]},"references-count":50,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2004]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.20102","relation":{},"ISSN":["0270-9139"],"issn-type":[{"value":"0270-9139","type":"print"}],"subject":[],"published":{"date-parts":[[2004,3]]}}}