NF-κB and STAT1 control CXCL1 and CXCL2 gene transcription

Abstract

Diabetes mellitus results from immune cell invasion into pancreatic islets of Langerhans, eventually leading to selective destruction of the insulin-producing ␤-cells. How this process is initiated is not well understood. In this study, we investigated the regulation of the CXCL1 and CXCL2 genes, which encode proteins that promote migration of CXCR2 ϩ cells, such as neutrophils, toward secreting tissue. Herein, we found that IL-1␤ markedly enhanced the expression of the CXCL1 and CXCL2 genes in rat islets and ␤-cell lines, which resulted in increased secretion of each of these proteins. CXCL1 and CXCL2 also stimulated the expression of specific integrin proteins on the surface of human neutrophils. Mutation of a consensus NF-B genomic sequence present in both gene promoters reduced the ability of IL-1␤ to promote transcription. In addition, IL-1␤ induced binding of the p65 and p50 subunits of NF-B to these consensus B regulatory elements as well as to additional B sites located near the core promoter regions of each gene. Additionally, serine-phosphorylated STAT1 bound to the promoters of the CXCL1 and CXCL2 genes. We further found that IL-1␤ induced specific posttranslational modifications to histone H3 in a time frame congruent with transcription factor binding and transcript accumulation. We conclude that IL-1␤-mediated regulation of the CXCL1 and CXCL2 genes in pancreatic ␤-cells requires stimulus-induced changes in histone chemical modifications, recruitment of the NF-B and STAT1 transcription factors to genomic regulatory sequences within the proximal gene promoters, and increases in phosphorylated forms of RNA polymerase II.

CXCR1/2 Inhibition Blocks and Reverses Type 1 Diabetes in Mice

“…This is in agreement with indirect evidence previously reported. Human pancreatic islets produce and secrete the proinflammatory CXCL8 and CXCL1 ligands (12,15,17,22,23), whereas lipopolysaccharide-induced production of CXCL8 by neutrophils is increased in prediabetic and T1D patients. In parallel, circulating concentrations of CXCL8 are elevated in children with T1D compared with nondiabetic controls (24)(25)(26).…”

“…In this study we hypothesized that CXCR1/2 inhibition may also be functional/effective in preventing inflammatory damage to pancreatic islets during diabetes development. In fact, pancreatic islets produce and secrete the CXCR1/2 chemokine ligands (named CXCL8, CXCL1, and CXCL2) in response to proinflammatory cytokines (12,15,17,22,23). Furthermore, the concentration of CXCR1/2 ligands is elevated in the blood of both rodents and humans with autoimmune diabetes (24)(25)(26); most important, recent reports support the notion that neutrophils (the major target of CXCR1/2 inhibitors) play a key role in the etiopathogenesis of T1D (27)(28)(29).…”

Thiobenzothiazole-modified Hydrocortisones Display Anti-inflammatory Activity with Reduced Impact on Islet β-Cell Function

“…Chemokines are a major subset of genes induced by inflammatory stimuli, such as IL-1␤ and palmitate, and probably contribute to immune cell infiltration and alterations in immune cell activity in both Type 1 and Type 2 diabetes mellitus (11)(12)(13)(14)(15). Thus, therapeutics capable of suppressing inflammatory responses in pancreatic islets with reduced impact on insulin secretion would be extremely valuable.…”

Insulitis and Diabetes: A Perspective on Islet Inflammation

“…Pancreatic β-cells express the IL-1RI at very high levels, some of the highest seen in any tissue, thus making them exquisitely sensitive to IL-1β [12][13][14]. Consequently, even at submaximal levels of IL-1RI activation, β-cells activate inflammatory pathways, including NF-κB, that initially re-program the cells at the transcriptional and metabolic levels followed by an eventual decline in their viability [15].…”

“…Consequently, even at submaximal levels of IL-1RI activation, β-cells activate inflammatory pathways, including NF-κB, that initially re-program the cells at the transcriptional and metabolic levels followed by an eventual decline in their viability [15]. Due to the high expression of the IL-1RI, the pancreatic β-cell is sensitive to picomolar amounts of IL-1β [13] and activation of this signaling mechanism is responsible for the expression of immunomodulatory chemokine genes [13,16,17]. A sustained release of chemokines from β-cells recruits immune cells into islets.…”