Increased tumour necrosis factor   production in mesenteric lymph nodes of cirrhotic patients with ascites

Abstract

Background: Cytokines produced in mesenteric lymph nodes of cirrhotic rats with bacterial translocation may participate in circulatory alterations of cirrhosis. Aim: To investigate whether cirrhotic patients present an increased local generation of cytokines in mesenteric lymph nodes. Methods: Mesenteric lymph nodes from 26 cirrhotic and 10 control patients were assessed for tumour necrosis factor α (TNF) and interleukin 6 mRNA and protein expression by competitive reverse transcription-polymerase chain reaction, and by enzyme immunoassay and immunohistochemistry, respectively. Results: Interleukin 6 levels were not different between cirrhotics and controls. Protein and mRNA TNF levels in mesenteric lymph nodes from cirrhotics were higher than in controls (p<0.05). Tissue expression of TNF by immunohistochemistry was more abundant in cirrhotics. Ascitic patients showed higher TNF levels (47 (34-54) pg/mg protein) than patients without ascites (18 (17-25) pg/mg protein) (p<0.001). Elevated TNF levels (>28 pg/mg protein) in cirrhotics were associated with a higher ChildPugh score, the antecedent of ascites, a lower prothrombin rate, and higher bilirubin and blood TNF levels. The strongest association, confirmed by multivariate analysis, was with the presence of ascites (p<0.001). Bacterial infections after transplantation, mainly by enteric bacteria, were only detected in patients with high TNF levels in mesenteric lymph nodes (33% of patients; p=0.05). Conclusion: Patients with advanced liver cirrhosis, and especially with ascites, have increased local production of TNF in mesenteric lymph nodes that, in common with experimental cirrhosis, may also be induced by bacterial translocation.

The detection of bacterial DNA in blood of rats with CCl4-induced cirrhosis with ascites represents episodes of bacterial translocation

“…Once dendritic cells reach MLNs, both B and T cells are activated to induce an immune response, and the intensity of this response may vary according to the viability of the bacteria carried by dendritic cells. 7 In fact, the synthesis of TNF-␣ in culture-positive MLNs in patients with cirrhosis and presence of AF is increased, 21 and MLNs are the site of initiation of the immune response by enteric bacteria. 22 As shown in Fig.…”

Bacterial translocation (BT) in cirrhosis

“…[69][70][71] Moreover, increased TNF production by MLN has also been reported in end-stage cirrhosis and has been associated with an increased incidence of bacterial infections after liver transplantation. 72 It is tempting to speculate that in cirrhosis, priming of mononuclear cells and associated release of pro-inflammatory cytokines is mediated by an upregulation of TLR expression.…”

Chronic antigenic stimuli as a possible explanation for the immunodepression caused by liver cirrhosis

“…In fact, this was our original hypothesis. Patients with increased LBP, a validated marker of endotoxaemia [11][12][13][14], present elevated serum levels of monocyte-derived cytokines or a higher percentage of regulatory T cells. It could be speculated that intestinal decontamination, for example with quinolones, could modify these altered factors.…”

“…LPS increases the plasma levels of LPS binding protein (LBP), the principal plasma protein responsible for transporting LPS to immune effector cells [11]. It has been proposed that high serum LBP identifies a subset of cirrhotic patients with ascites characterized by the immune cells being activated to produce tumour necrosis factor (TNF)-a and other proinflammatory cytokines [12][13][14][15]. Moreover, raised levels of circulating LBP or proinflammatory cytokines have been implicated in the endothelial activation and haemodynamic derangement observed in cirrhosis [12,16].…”