Abstract

Background: Recent data have indicated that decompensated cirrhosis is characterized by an imbalance in the innate immune system, leading to low-grade systemic inflammation. In particular, inflammatory cytokines secreted by monocytes and macrophages have been implicated in the pathogenesis of portal hypertension and its complications. Additionally, MerTK-expressing monocytes participate in the determination of severity of acute liver failure. Trans-jugular intrahepatic portosystemic shunt (TIPS) is currently used for the treatment of complications of portal hypertension, but whether portosystemic derivation results in changes in the biology of inflammatory cell is currently unknown.

Methods: Fifteen patients with severe portal hypertension referred for TIPS placement were enrolled. During the TIPS procedure, blood from the portal and jugular vein was drawn, and at 4 weeks after TIPS placement a sample from a peripheral vein was repeated. Monocytes were isolated from peripheral blood mononuclear cells by adherence after Ficoll-Hypaque purification, and stimulated with LPS (1 μg/ml) for 2, 8 and 24 hours. Gene expression was evaluated by real-time PCR.

Results: Upon exposure to LPS, a significant increase in gene expression of IL-1beta, IL-6, TLR4 and MERTK was observed in monocytes isolated from either the portal or the jugular vein. Basal and LPS-stimulated mRNA levels of these molecules were markedly lower in the post-TIPS compared to pre- TIPS, in particular after exposure to LPS. Expression of the anti-inflammatory cytokine, IL-10, was significantly increased after LPS stimulation for 2 and 8 hours. After TIPS, mRNA levels of IL-10 were reduced in unstimulated conditions but increased after LPS stimulation for 2 hours.

Conclusion: Reduction of portal pressure through TIPS placement is associated with reduced expression of pro-inflammatory mediators and modulation of anti-inflammatory IL-10. Increased portal pressure in cirrhotic patients may be a direct modulator of the complex changes in the inflammatory balance observed in these patients