IL-1β priming triggers an adaptive stress response that enhances pancreatic β-cell resilience to subsequent cytotoxic inflammatory insult

In this study, we explored the role of IL-1β-mediated hormesis in defending β-cells against dysfunction and death induced by pro-inflammatory cytokines (CYT). Preconditioning β-cells with physiological circulating levels of IL-1β (IL-1βlow) induced a resilient state, protecting them from CYT-induced cell death while preserving glucose-stimulated insulin secretion through hormesis. IL-1βlow-treated INS-1E cells reduced CYT-induced NO secretion by suppressing NF-κB signaling and decreasing iNOS expression, correlating with reduced β-cell death. IL-1βlow conditioning reduced ER stress and upregulated p-eIF2a in response to CYT, thereby enhancing the expression of ER chaperones and biomarkers linked to improved β-cell identity/functionality. RNA-seq profiling of INS-1E cells conditioned with IL-1β 10 pg/ml for 72h (IL-1βlow), with fresh cytokine added every 24h without replacing the culture media. Then, the culture media was renewed, and cells were challenged with a proinflammatory cytokine mixture (CYT: IL-1β 100 pg/ml + IFN-γ 5 ng/ml) for 16h. Experimental conditons: untreated, IL-1βlow, CYT, IL-1βlow + CYT. Three biological replicates were included for each condition.