Effect of Inflammatory cytokines on ER homeostasis, proinsulin folding and trafficking
Abstract
Inflammatory cytokines are signaling molecules secreted by immune cells that profoundly influence pancreatic β-cell physiology. In β cells, exposure to these cytokines often triggers stress responses that impair insulin synthesis and promote cellular dysfunction, contributing to diabetes development. However, the link between cytokine signaling and proinsulin folding, the critical precursor step in insulin production, remains poorly understood. In this study, we examined how individual and combined inflammatory cytokines (TNF-α, IFN-γ, and IL-1β) affect β-cell homeostasis, focusing on both endoplasmic reticulum (ER) and mitochondrial health. Treatment of INS1 β cells with the cytokine cocktail for 24 hours nearly eliminated proinsulin content and secretion, suggesting a strong biosynthetic defect. After 48 hours, live-cell imaging revealed widespread cell death, though surviving cells exhibited normal levels of proinsulin granules. ROS measurements using the DCF assay showed a marked increase under cytokine cocktail treatment compared to control and single-cytokine conditions, indicating oxidative stress and mitochondrial dysfunction. Additionally, expression of BiP, a key ER chaperone essential for proinsulin folding, was significantly reduced, suggesting that cytokine exposure compromises ER protein-folding capacity. Based on these findings, we infer that prolonged inflammatory stress disrupts both ER and mitochondrial integrity, potentially reducing ATP availability required for efficient protein folding. The combined cytokines appear to synergistically impair β-cell function by disturbing intracellular organelle communication and proteostasis, leading to defective proinsulin maturation and secretion. These results provide insight into how inflammatory cytokine interactions accelerate β-cell stress and may represent an early cellular mechanism linking inflammation to diabetes pathogenesis. Future work will aim to identify the specific molecular pathways connecting ER dysfunction, mitochondrial stress, and altered protein-folding dynamics in cytokine-exposed β cells.
Start Time
15-4-2026 9:00 AM
End Time
15-4-2026 12:00 PM
Room Number
Culp Ballroom 316
Poster Number
32
Presentation Type
Poster
Presentation Subtype
Posters - Competitive
Presentation Category
Science, Technology, and Engineering
Student Type
Graduate and Professional Degree Students, Residents, Fellows
Faculty Mentor
Anoop Arunagiri
Effect of Inflammatory cytokines on ER homeostasis, proinsulin folding and trafficking
Culp Ballroom 316
Inflammatory cytokines are signaling molecules secreted by immune cells that profoundly influence pancreatic β-cell physiology. In β cells, exposure to these cytokines often triggers stress responses that impair insulin synthesis and promote cellular dysfunction, contributing to diabetes development. However, the link between cytokine signaling and proinsulin folding, the critical precursor step in insulin production, remains poorly understood. In this study, we examined how individual and combined inflammatory cytokines (TNF-α, IFN-γ, and IL-1β) affect β-cell homeostasis, focusing on both endoplasmic reticulum (ER) and mitochondrial health. Treatment of INS1 β cells with the cytokine cocktail for 24 hours nearly eliminated proinsulin content and secretion, suggesting a strong biosynthetic defect. After 48 hours, live-cell imaging revealed widespread cell death, though surviving cells exhibited normal levels of proinsulin granules. ROS measurements using the DCF assay showed a marked increase under cytokine cocktail treatment compared to control and single-cytokine conditions, indicating oxidative stress and mitochondrial dysfunction. Additionally, expression of BiP, a key ER chaperone essential for proinsulin folding, was significantly reduced, suggesting that cytokine exposure compromises ER protein-folding capacity. Based on these findings, we infer that prolonged inflammatory stress disrupts both ER and mitochondrial integrity, potentially reducing ATP availability required for efficient protein folding. The combined cytokines appear to synergistically impair β-cell function by disturbing intracellular organelle communication and proteostasis, leading to defective proinsulin maturation and secretion. These results provide insight into how inflammatory cytokine interactions accelerate β-cell stress and may represent an early cellular mechanism linking inflammation to diabetes pathogenesis. Future work will aim to identify the specific molecular pathways connecting ER dysfunction, mitochondrial stress, and altered protein-folding dynamics in cytokine-exposed β cells.
