Mesenteric Th1 polarization and monocyte TNF-α production: First steps to systemic inflammation in rats with cirrhosis

Authors

  • Leticia Muñoz,

    1. Laboratorio de Enfermedades del Sistema Inmune, Unidad I+D Asociada al Centro Nacional de Biotecnología (CSIC), Departamento de Medicina, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain
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    • L.M. and A.A. contributed equally to this article.

  • Agustín Albillos,

    Corresponding author
    1. Laboratorio de Enfermedades del Sistema Inmune, Unidad I+D Asociada al Centro Nacional de Biotecnología (CSIC), Departamento de Medicina, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain
    2. Servicio de Gastroenterología, Hospital Universitario Ramón y Cajal, Madrid, Spain
    • Departamento de Medicina, Facultad de Medicina-Campus Universitario, Universidad de Alcalá, Carretera Madrid-Barcelona km. 33.600, 28871 Alcalá de Henares, Madrid, Spain
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    • L.M. and A.A. contributed equally to this article.

    • fax: (34) 91 8854526

  • Mónica Nieto,

    1. Laboratorio de Enfermedades del Sistema Inmune, Unidad I+D Asociada al Centro Nacional de Biotecnología (CSIC), Departamento de Medicina, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain
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  • Eduardo Reyes,

    1. Laboratorio de Enfermedades del Sistema Inmune, Unidad I+D Asociada al Centro Nacional de Biotecnología (CSIC), Departamento de Medicina, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain
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  • Lourdes Lledó,

    1. Departamento de Microbiología, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain
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  • Jorge Monserrat,

    1. Laboratorio de Enfermedades del Sistema Inmune, Unidad I+D Asociada al Centro Nacional de Biotecnología (CSIC), Departamento de Medicina, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain
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  • Eva Sanz,

    1. Laboratorio de Enfermedades del Sistema Inmune, Unidad I+D Asociada al Centro Nacional de Biotecnología (CSIC), Departamento de Medicina, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain
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  • Antonio de la Hera,

    1. Laboratorio de Enfermedades del Sistema Inmune, Unidad I+D Asociada al Centro Nacional de Biotecnología (CSIC), Departamento de Medicina, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain
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  • Melchor Alvarez-Mon

    1. Laboratorio de Enfermedades del Sistema Inmune, Unidad I+D Asociada al Centro Nacional de Biotecnología (CSIC), Departamento de Medicina, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain
    2. Servicio de Enfermedades del Sistema Inmune y Oncología, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain
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  • Potential conflict of interest: Nothing to report.

Abstract

A systemic inflammatory state with increased circulating tumor necrosis factor alpha (TNF-α) has been related to the bacterial infection susceptibility and hemodynamic derangement of patients with cirrhosis. We compared the activation status of immune cell subpopulations defined by 4-color cytometry in mesenteric and peripheral lymph nodes and blood of rats with CCl4-cirrhosis to define the immune response initiation site, the T-cell and monocyte contribution to pro-inflammatory cytokine production, as well as the pathogenic role of enteric bacteria in the cirrhosis immune response. Th1 cells and monocytes were expanded in the mesenteric nodes (P < .001) and blood (P < .001) of rats with cirrhosis, and activated to produce interferon gamma (P < .0001) and TNF-α (P < .0001), respectively. The greater numbers of recently activated CD134+ Th cells in mesenteric nodes compared with blood, the correlation between their numbers in mesenteric nodes and blood (r = 0.66, P < .001), and the expansion of activated CD45RC Th cells, which are unable to re-enter lymph nodes, in mesenteric nodes but not in blood or axillary nodes points to mesenteric nodes as the origin site of activated Th cells. Abrogation of bacterial translocation by bowel decontamination reduced the number of activated Th cells and monocytes, and normalized interferon gamma production by Th cells and TNF-α production by monocytes in mesenteric nodes and blood, respectively. In conclusion, in cirrhosis, enteric bacteria start off an orchestrated immune response cascade in mesenteric nodes involving Th1 polarization and monocyte activation to TNF-α production. Later, the recirculation of these activated effector immune cells into blood promotes systemic inflammation. (HEPATOLOGY 2005;42:411–419.)

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