My SCS liver has high IL-18 levels. Is this consistent with other data?
High levels of Interleukin-18 (IL-18) in livers preserved via static cold storage (SCS) are consistent with existing data regarding ischemia-reperfusion injury (IRI) and graft inflammation. IL-18 serves as an early, sensitive indicator of cell damage and caspase-1 activation, with levels correlating significantly with the duration of cold ischemia and the severity of subsequent reperfusion injury.
IL-18 as a Biomarker of Static Cold Storage Injury
Livers subjected to prolonged SCS exhibit significantly higher release of IL-18 upon reperfusion compared to livers with minimal storage or those preserved via machine perfusion.
* Kinetics of Release: In a porcine model, IL-18 levels in perfusates increased rapidly after reperfusion following 20 hours of SCS, reaching an early peak of 11,012.0 pg/ml at 2 hours, whereas control grafts (no prolonged SCS) remained stable at 1,493.0 pg/ml (Direct, High; PMID: 36338535).
* Storage Duration Dependency: IL-18 protein expression is significantly more elevated in donor livers preserved by SCS than in those treated with hypothermic machine perfusion (HMP) (Direct, High; PMID: 41645764).
* Predictive Value: IL-18 and High-Mobility-Group-Protein B1 (HMGB1) are identified as early indicators for cell damage during normothermic machine perfusion (NMP) following prolonged cold ischemic storage (Direct, High; PMID: 36338535).
Correlation with Graft Inflammation and Injury
Elevated IL-18 levels are directly linked to the inflammatory cascade and parenchymal damage characteristic of hepatic IRI.
* Cellular Source and Effect: IL-18 is generated mainly from leukocytes and promotes inflammation in liver tissue, eventually inducing hepatocyte cell death at late stages of IRI (Direct, High; PMID: 35438583).
* Organ Damage Association: IL-18 secretion kinetics peak similarly to Gamma-glutamyltransferase (GGT), suggesting a strong association between IL-18 and bile duct inflammation or injury following prolonged SCS (Direct, High; PMID: 36338535).
* Immune Cell Recruitment: High IL-18 concentrations promote the infiltration of natural killer (NK) cells into the graft paravalvular regions, contributing to acute vascular rejection (Direct, High; PMID: 36551229, PMID: 35418990).
* Systemic Implications: High IL-18 levels are associated with poor clinical outcomes, including acute-on-chronic liver failure (ACHBLF) and acute kidney injury following liver transplantation (Direct, High; PMID: 40538651, PMID: 23327592).
Mechanisms of IL-18 Activation in IRI
The release of mature IL-18 is dependent on the activation of intracellular machinery triggered during the cold-to-warm transition.
* Inflammasome Dependency: IL-18 is a caspase-cleavage-dependent cytokine; its release indicates activation of caspase-1 via the NLRP3 inflammasome, which is primed by danger-associated molecular patterns (DAMPs) released during SCS (Direct, High; PMID: 36338535, PMID: 38908436).
* Regulatory Pathways: Activation of the AXL signaling pathway can suppress the NLRP3 inflammasome, thereby reducing serum IL-18 levels and attenuating IRI (Direct, High; PMID: 41087895).
* Remote Organ Effects: Renal allograft IRI can initiate remote hepatic injury characterized by increased histone release, which binds to TLR-4/TLR-9 to trigger NLRP3 activation and subsequent IL-18 production in the liver (Indirect, Medium; PMID: 29446207).
Therapeutic Modulation of IL-18
Strategies aiming to reduce IL-18 levels or its biological activity have demonstrated protective effects against graft injury.
* IL-18 Binding Protein (IL-18BP): Overexpression of IL-18BP, a natural inhibitor of IL-18, significantly reduces inflammatory factor expression (IFN-γ, TNF-α, IL-6), decreases hepatocyte apoptosis, and improves graft survival (Direct, High; PMID: 36551229).
* Machine Perfusion: Both hypothermic and normothermic machine perfusion techniques reduce the accumulation and peak release of IL-18 compared to standard SCS by maintaining mitochondrial integrity and potentially washing out inflammatory mediators (Derived, High; PMID: 36338535, PMID: 41645764).
Unverified Citations
The following sources failed to support their assigned claims after 3 verification rounds designed to ensure only high-confidence, relevant references are retained:
- PMID:36338535 — ** IL-18 Binding Protein (IL-18BP): Overexpression of IL-18BP, a natural inhibitor of IL-18, significantly reduces ...*
Failed: entities,conclusion — The paper mentions IL-18 blockade results in other studies but does not study IL-18BP overexpression or provide data for the specific outcomes claimed.