Mesenteric Th1 polarization and monocyte TNF-α production: First steps to systemic inflammation in rats with cirrhosis
✍ Scribed by Leticia Muñoz; Agustín Albillos; Mónica Nieto; Eduardo Reyes; Lourdes Lledó; Jorge Monserrat; Eva Sanz; Antonio de la Hera; Melchor Alvarez-Mon
- Publisher
- John Wiley and Sons
- Year
- 2005
- Tongue
- English
- Weight
- 246 KB
- Volume
- 42
- Category
- Article
- ISSN
- 0270-9139
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✦ Synopsis
A systemic inflammatory state with increased circulating tumor necrosis factor alpha (TNF-␣) 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-␣ (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-␣ 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-␣ production. Later, the recirculation of these activated effector immune cells into blood promotes systemic inflammation. (HEPATOLOGY 2005;42:411-419.)
P atients with cirrhosis and ascites suffer a systemic inflammatory state that features blood lymphocyte and monocyte activation and an increased production of pro-inflammatory cytokines. [1][2][3] Immune abnormalities in cirrhosis with ascites include diminished absolute numbers of naive and memory T cells, an increased percentage of activated T cells, and markedly increased numbers of activated monocytes in peripheral blood. [1][2][3][4] Notably, monocytes spontaneously produce tumor necrosis factor alpha (TNF␣), 3 a pro-inflammatory cytokine that has been implicated in the hemodynamic derangement of cirrhosis. 2,[5][6][7] The sites of activation of these circulating immune cells have not been established. However, immune system activation in cirrhosis might be promoted by enteric bacterial products, as suggested by its relationship with bacterial translocation to mesenteric lymph nodes (MLNs), 7-9 its amelioration by intestinal decontamination with antibiotics, 2,10 and its association with an augmented risk of spontaneous bacterial infection in patients with high plasma levels of lipopolysaccharidebinding protein. 11