ArticlebioRxiv : the preprint server for biology2024
DOC2b enrichment mitigates proinflammatory cytokine-induced CXCL10 expression by attenuating IKKβ and STAT-1 signaling in human islets.
Article in bioRxiv : the preprint server for biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Introduction: Type 1 diabetic human islet β-cells are deficient in double C 2 like domain beta (DOC2b) protein. Further, DOC2b protects against cytokine-induced pancreatic islet β-cell stress and apoptosis. However, the mechanisms underpinning the protective effects of DOC2b remain unknown. Methods: Biochemical studies, qPCR, proteomics, and immuno-confocal microscopy were conducted to determine the underlying protective mechanisms of DOC2b in β-cells. DOC2b- enriched or-depleted primary islets (human and mouse) and β-cell lines challenged with or without proinflammatory cytokines, global DOC2b heterozygous knockout mice subjected to multiple-low-dose-streptozotocin (MLD-STZ), were used for these studies. Results: A significant elevation of stress-induced CXCL10 mRNA was observed in DOC2b- depleted β-cells and primary mouse islets. Further, DOC2b enrichment markedly attenuated cytokine-induced CXCL10 levels in primary non-diabetic human islets and β-cells. DOC2b enrichment also reduced total-NF-κB p65 protein levels in human islets challenged with T1D mimicking proinflammatory cytokines. IKKβ, NF-κB p65, and STAT-1 are capable of associating with DOC2b in cytokine-challenged β-cells. DOC2b enrichment in cytokine-stressed human islets and β-cells corresponded with a significant reduction in activated and total IKKβ protein levels. Total IκBβ protein was increased in DOC2b-enriched human islets subjected to acute cytokine challenge. Cytokine-induced activated and total STAT-1 protein and mRNA levels were markedly reduced in DOC2b-enriched human islets. Intriguingly, DOC2b also prevents ER-stress-IKKβ and STAT-1 crosstalk in the rat INS1-832/13 β-cell line. Conclusion: The mechanisms underpinning the protective effects of DOC2b involve attenuation of IKKβ-NF-κB p65 and STAT-1 signaling, and reduced CXCL10 expression. Graphical abstract:
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