Expression signatures of IL-18 and IL-18BP characterize stages of cirrhotic decompensation

Background: Cirrhosis-associated immune dysfunction (CAID) favors infections and organ dysfunction to precipitate acute-on chronic liver failure (ACLF). Molecular CAID networks remain unresolved, but may include IL-18, a potent inflammatory cytokine and cell death modulator, and its antagonist IL-18BP as targetable agents.

Aim: To delineate patterns of IL-18 and IL-18BP expression in decompensated cirrhosis (DC) and ACLF, and to assess their relations to established inflammatory markers and disease severity in humans.

Methods: Hepatic mRNA expression was quantified via RNAseq. Plasma IL-18, IL-18BP, sCD14, LBP and iFABP levels were measured via ELISA in a prospective cohort of 111 cirrhosis patients (75 with ACLF), and correlated with CRP, IL-6, WBC and NLR, organ dysfunction, and outcomes.

Results: IL-18 and IL-18BP are increasingly upregulated in DC and ACLF livers. Circulating IL-18 increases with progressive hepatic decompensation independently of cirrhosis etiology, and a particularly high IL-18/IL-18BP ratio characterizes ACLF. IL-18 more robustly correlates with ACLF grade, MELD, MELD-Na and Child-Pugh scores than CRP, IL-6, WBC and NLR. IL-18, IL-6, WBC and NLR are significantly lower in ACLF survivors compared to non-survivors and patients requiring liver transplantation, whereas CRP and IL-18BP are not. Correlation between IL-18 and IL-18BP with IL-6 were only moderate (<0,5), and remarkably low with markers of intestinal barrier dysfunction.

Conclusion: IL-18 induction characterizes hepatic decompensation, with expression patterns distinct from IL-6, WBC, CRP and NLR. In ACLF, an IL-18/IL-18BP imbalance inferred by relative IL-18BP underabundance may drive organ dysfunction and affect outcomes. The specific contributions of IL-18 to CAID mandate further.

Publication History

Article published online:
20 January 2025