title: 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 β-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(+) cells, such as neutrophils, toward secreting tissue. Herein, we found that IL-1β markedly enhanced the expression of the CXCL1 and CXCL2 genes in rat islets and β-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-κB genomic sequence present in both gene promoters reduced the ability of IL-1β to promote transcription. In addition, IL-1β induced binding of the p65 and p50 subunits of NF-κB to these consensus κB regulatory elements as well as to additional κB 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-1β induced specific posttranslational modifications to histone H3 in a time frame congruent with transcription factor binding and transcript accumulation. We conclude that IL-1β-mediated regulation of the CXCL1 and CXCL2 genes in pancreatic β-cells requires stimulus-induced changes in histone chemical modifications, recruitment of the NF-κB and STAT1 transcription factors to genomic regulatory sequences within the proximal gene promoters, and increases in phosphorylated forms of RNA polymerase II.
authors.affiliation: Department of Nutrition, University of Tennessee, Knoxville, Tennessee;
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Burke
authors.forename: Danhong
authors.initials: D
authors.lastname: Lu
authors.forename: Tim E
authors.initials: TE
authors.lastname: Sparer
authors.forename: Thomas
authors.initials: T
authors.lastname: Masi
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Goff
authors.forename: Michael D
authors.initials: MD
authors.lastname: Karlstad
authors.forename: J Jason
authors.initials: JJ
authors.lastname: Collier
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D054360:Chemokine CXCL1 / Q000235:genetics*; D054426:Chemokine CXCL2 / Q000235:genetics*; D005786:Gene Expression Regulation; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D053583:Interleukin-1beta / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; C513297:Cxcl1 protein, rat; C513296:Cxcl2 protein, rat; D053583:Interleukin-1beta; D016328:NF-kappa B; D050794:STAT1 Transcription Factor; C494081:Stat1 protein, rat