Mesenteric Th1 polarization and monocyte TNF-alpha production: first steps to systemic inflammation in rats with cirrhosis.
A systemic inflammatory state with increased circulating tumor necrosis factor alpha (TNF-alpha) 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 CCl(4)-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-alpha (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-alpha 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-alpha production. Later, the recirculation of these activated effector immune cells into blood promotes systemic inflammation.
Muñoz
Leticia
L
Laboratorio de Enfermedades del Sistema Inmune, Unidad I+D Asociada al Centro Nacional de Biotecnología (CSIC), Departamento de Medicina, Universidad de Alcalá, 28871 Alcalá de Henares, Madrid, Spain.
Albillos
Agustín
A
Nieto
Mónica
M
Reyes
Eduardo
E
Lledó
Lourdes
L
Monserrat
Jorge
J
Sanz
Eva
E
de la Hera
Antonio
A
Alvarez-Mon
Melchor
M
D000818:Animals; D016764:Cell Polarity; D007249:Inflammation / Q000209:etiology* / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D008106:Liver Cirrhosis, Experimental / Q000276:immunology*; D008198:Lymph Nodes / Q000276:immunology; D008297:Male; D008643:Mesentery / Q000276:immunology*; D009000:Monocytes / Q000276:immunology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018417:Th1 Cells / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma