Inflammation-induced NFκB activation drives pro-inflammatory and anti-apoptotic transcriptome in mouse islets

Diabetes results from an inflammatory insult to the pancreas. NFκB is a key transcription factor regulating cellular inflammatory responses. Therefore, we hypothesized that inflammatory exposures would acutely activate NFκB in the adult mouse pancreas and in isolated islets, leading to upregulation of target genes associated with inflammation and apoptosis. Mice were exposed to lipopolysaccharide (LPS) and isolated islets were exposed to a cytokine mixture to model a strong pro-inflammatory challenge. NFκB activation was determined by phosphorylation and nuclear translocation of NFκB proteins p65 and p50, dynamics of the inhibitors, IκBα and IκBβ, and the expression of NFκB target genes. NFκB target gene transcription was then correlated with p65 binding at promoter regions. Targeted apoptotic transcriptome changes were also evaluated. Systemic LPS exposure induced pancreatic NFκB activation, as evidenced by IκB oscillations and nuclear translocation of NFκB subunits. In isolated islets, cytokines triggered rapid p65 phosphorylation and DNA binding and increased NFκB target gene expression, with corresponding increases in specific promoter binding. Notably, anti-apoptotic genes were upregulated. These findings demonstrate that acute inflammatory stress activates NFκB in pancreatic tissue and islets, promoting a pro-inflammatory yet anti-apoptotic transcriptional response. Targeting NFκB at specific timepoints after inflammation may help prevent β-cell injury and diabetes development.