Interleukin-39 is a Prognostic Biomarker and Therapy Target for Sepsis.

Summary

Across two independent patient cohorts, circulating IL-39 was elevated at sepsis presentation and predicted 28-day survival. Single-cell and mouse experiments identified macrophage-derived IL-39 as a causal aggravator of sepsis through GP130-dependent MAPK/P38 signaling; genetic suppression or antibody neutralization was protective.

Key Findings

• Serum IL-39 was significantly increased in septic patients across two independent cohorts and predicted 28-day survival.
• Single-cell sequencing localized the increased IL-39 signal primarily to macrophages.
• Recombinant IL-39 or macrophage-specific overexpression worsened sepsis in mice, whereas macrophage-specific deficiency, silencing, or neutralizing antibodies were protective.
• IL-39 aggravated inflammation through GP130-mediated MAPK/P38 signaling, and macrophage-specific GP130 deletion abrogated this effect.

Clinical Implications

Serum IL-39 could potentially support prognostic stratification at admission, while IL-39 neutralization or interruption of the IL-39–GP130 pathway may represent a future adjunctive therapy. Clinical use requires prospective validation, dose and timing studies, and confirmation of safety because excessive immune suppression could impair host defense.

Limitations

• The clinical biomarker findings are prognostic associations and do not establish that IL-39 measurement improves patient outcomes.
• The therapeutic experiments were conducted in septic mice, so human pharmacology, optimal treatment timing, and safety remain unestablished.

Future Directions

Prospective multicenter studies should validate IL-39 thresholds and incremental value beyond established severity scores. Translation should proceed through biomarker-enriched clinical trials of IL-39 or GP130 inhibition, with careful monitoring of pathogen clearance and secondary infections.