Downregulation of interleukine-6 receptors on ascitic T cells may shape the immune compartment in the peritoneal cavity

Background and Aims In patients with advanced liver cirrhosis, high cytokine levels in ascites indicate a dysregulated overshooting immune response in the peritoneal cavity. While it is already known that impaired intestinal permeability and bacterial translocation are triggers for this hyperinflammation, the resulting cellular mechanisms are not yet sufficiently understood. This study aims to analyze the effect of dysregulated interleukin-6 (IL-6) signaling on the T cell compartment in ascites.

Methods Ascites and peripheral blood samples from patients with liver cirrhosis were collected and immune cells were isolated. Cytokine and soluble receptor concentrations were determined by ELISA. T cell phenotype and surface receptor expression was assessed by flow cytometry.

Results In ascites, the natural IL-6 trans-signaling inhibitor soluble gp130 was found to be 14.4-fold higher than the soluble IL-6 receptor (IL-6R), suggesting that IL-6 trans-signaling is blocked. The surface expression of IL-6R and gp130 was significantly lower among T cells within ascites compared to those circulating in blood (P=0.009 and P=0.036, respectively). Overall, IL-6 classical-signaling reactive gp130+IL-6R+T cells were significantly decreased in ascites compared to blood (P=0.019). However, CD4+Th17 cells, whose differentiation is dependent on IL-6, were significantly more enriched in ascites than in blood (P=0.0025).

Conclusion We suggest that the blockade of trans-signaling and downregulation of IL-6 surface receptors on T cells may represent compensatory mechanisms to mitigate excessive IL-6 signaling induced by high IL-6 levels in ascites. Nevertheless, IL-6 signaling seems to shape the immune compartment in the peritoneal cavity and thus may contribute to systemic hyperinflammation.

Publication History

Article published online:
20 January 2025