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CXCL10 promotes liver fibrosis by prevention of NK cell mediated hepatic stellate cell inactivation.
Hintermann, Edith; Bayer, Monika; Pfeilschifter, Josef M; Luster, Andrew D; Christen, Urs.
Afiliação
  • Hintermann E; Pharmazentrum Frankfurt/ZAFES, Johann Wolfgang Goethe University, Frankfurt am Main, Germany.
J Autoimmun ; 35(4): 424-35, 2010 Dec.
Article em En | MEDLINE | ID: mdl-20932719
ABSTRACT
Chemokines, such as CXCL10, promote hepatic inflammation in chronic or acute liver injury through recruitment of leukocytes to the liver parenchyma. The CXCL10 receptor CXCR3, which is expressed on a subset of leukocytes, plays an important part in Th1-dependent inflammatory responses. Here, we investigated the role of CXCL10 in chemically induced liver fibrosis. We used carbon tetrachloride (CCl(4)) to trigger chronic liver damage in wildtype C57BL/6 and CXCL10-deficient mice. Fibrosis severity was assessed by Sirius Red staining and intrahepatic leukocyte subsets were investigated by immunohistochemistry. We have further analyzed hepatic stellate cell (HSC) distribution and activation and investigated the effect of CXCL10 on HSC motility and proliferation. In order to demonstrate a possible therapeutic intervention strategy, we have examined the anti-fibrotic potential of a neutralizing anti-CXCL10 antibody. Upon CCl(4) administration, CXCL10-deficient mice showed massively reduced liver fibrosis, when compared to wildtype mice. CXCL10-deficient mice had less B- and T lymphocyte and dendritic cell infiltrations within the liver and the number and activity of HSCs was reduced. In contrast, natural killer (NK) cells were more abundant in CXCL10-deficient mice and granzyme B expression was increased in areas with high numbers of NK cells. Further detailed analysis revealed that HSCs express CXCR3, respond to CXCL10 and secrete CXCL10 when stimulated with IFNγ. Blockade of CXCL10 with a neutralizing antibody exhibited a significant anti-fibrotic effect. Our data suggest that CXCL10 is a pro-fibrotic factor, which participates in a crosstalk between hepatocytes, HSCs and immune cells. NK cells seem to play an important role in controlling HSC activity and fibrosis. CXCL10 blockade may constitute a possible therapeutic intervention for hepatic fibrosis.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Células Matadoras Naturais / Quimiocina CXCL10 / Células Estreladas do Fígado / Fígado / Cirrose Hepática Limite: Animals Idioma: En Revista: J Autoimmun Assunto da revista: ALERGIA E IMUNOLOGIA Ano de publicação: 2010 Tipo de documento: Article País de afiliação: Alemanha

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Células Matadoras Naturais / Quimiocina CXCL10 / Células Estreladas do Fígado / Fígado / Cirrose Hepática Limite: Animals Idioma: En Revista: J Autoimmun Assunto da revista: ALERGIA E IMUNOLOGIA Ano de publicação: 2010 Tipo de documento: Article País de afiliação: Alemanha