Between Fire and Restraint: Context-Dependent Roles of Interleukins 27, 33, 35 and 37 in Acute Pancreatitis

Interleukins 27 (IL-27), 33 (IL-33), 35 (IL-35) and 37 (IL-37) occupy potentially important but biologically non-equivalent positions at the interface between inflammatory amplification, tissue protection and immune restraint in acute pancreatitis (AP). This narrative review critically synthesizes AP-specific evidence, distinguishing mechanistic participation from biomarker association and defining translational priorities.

PubMed/MEDLINE, Scopus and Google Scholar were searched through July 2026. The review was structured with reference to the Scale for the Assessment of Narrative Review Articles (SANRA). Of 215 records identified, 43 underwent full-text assessment and 35 were included in the narrative synthesis (32 original studies and 3 reviews). Primary AP studies were prioritized, with landmark mechanistic studies used to interpret cytokine biology.

IL-33/ST2 was the most extensively studied axis and showed phase-, compartment- and molecular-form-dependent effects. Soluble ST2 correlated with severity but has not been validated for incremental prediction. IL-37 had the strongest direct protective evidence, inhibiting NLRP3-caspase-1-gasdermin D-mediated acinar-cell pyroptosis experimentally and showing an inverse association with pancreatic necrosis in patients; however, this clinical association derived from a single cohort and requires external validation. IL-35 findings were contradictory, with both severity-associated increases and reduced concentrations reported; assay characteristics may limit reliable distinction of intact bioactive IL-35 from free subunits or related complexes. Evidence for IL-27 was sparse and largely indirect. Across all four cytokines, clinical evidence remains limited by small or heterogeneous cohorts, inconsistent timing and analytical methods, and insufficient independent validation.

These cytokines should not be considered a uniform anti-inflammatory group. IL-33/ST2 is context-dependent, IL-37 is a promising but preclinical cytoprotective candidate, and IL-35 and IL-27 remain hypothesis-generating. None is validated as a stand-alone biomarker or therapeutic target for routine AP care. Further progress requires standardized assays, longitudinal sampling and independent clinical validation.