title: CCL20 is elevated during obesity and differentially regulated by NF-κB subunits in pancreatic β-cells.
abstract: Enhanced leukocytic infiltration into pancreatic islets contributes to inflammation-based diminutions in functional β-cell mass. Insulitis (aka islet inflammation), which can be present in both T1DM and T2DM, is one factor influencing pancreatic β-cell death and dysfunction. IL-1β, an inflammatory mediator in both T1DM and T2DM, acutely (within 1h) induced expression of the CCL20 gene in rat and human islets and clonal β-cell lines. Transcriptional induction of CCL20 required the p65 subunit of NF-κB to replace the p50 subunit at two functional κB sites within the CCL20 proximal gene promoter. The NF-κB p50 subunit prevents CCL20 gene expression during unstimulated conditions and overexpression of p50 reduces CCL20, but enhances cyclooxygenase-2 (COX-2), transcript accumulation after exposure to IL-1β. We also identified differential recruitment of specific co-activator molecules to the CCL20 gene promoter, when compared with the CCL2 and COX2 genes, revealing distinct transcriptional requirements for individual NF-κB responsive genes. Moreover, IL-1β, TNF-α and IFN-γ individually increased the expression of CCR6, the receptor for CCL20, on the surface of human neutrophils. We further found that the chemokine CCL20 is elevated in serum from both genetically obese db/db mice and in C57BL6/J mice fed a high-fat diet. Taken together, these results are consistent with a possible activation of the CCL20-CCR6 axis in diseases with inflammatory components. Thus, interfering with this signaling pathway, either at the level of NF-κB-mediated chemokine production, or downstream receptor activation, could be a potential therapeutic target to offset inflammation-associated tissue dysfunction in obesity and diabetes.
authors.affiliation: Laboratory of Islet Biology and Inflammation, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA; Department of Nutrition, University of Tennessee, Knoxville, Knoxville, TN 37996, USA.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Burke
authors.affiliation: Department of Surgery, Graduate School of Medicine, University of Tennessee Medical Center, Knoxville, TN, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Karlstad
authors.affiliation: Department of Surgery, Graduate School of Medicine, University of Tennessee Medical Center, Knoxville, TN, USA.
authors.forename: Kellie M
authors.initials: KM
authors.lastname: Regal
authors.affiliation: Department of Microbiology, University of Tennessee, Knoxville, Knoxville, TN 37996, USA.
authors.forename: Tim E
authors.initials: TE
authors.lastname: Sparer
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC 27704, USA.
authors.forename: Danhong
authors.initials: D
authors.lastname: Lu
authors.affiliation: Adipocyte Biology Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA.
authors.forename: Carrie M
authors.initials: CM
authors.lastname: Elks
authors.affiliation: Adipocyte Biology Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA.
authors.forename: Ryan W
authors.initials: RW
authors.lastname: Grant
authors.affiliation: Adipocyte Biology Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA.
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Stephens
authors.affiliation: Cell Biology and Bioimaging Core Facility, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Burk
authors.affiliation: Laboratory of Islet Biology and Inflammation, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA; Department of Nutrition, University of Tennessee, Knoxville, Knoxville, TN 37996, USA; Department of Surgery, Graduate School of Medicine, University of Tennessee Medical Center, Knoxville, TN, USA. Electronic address: Jason.collier@pbrc.edu.
authors.forename: J Jason
authors.initials: JJ
authors.lastname: Collier
mesh_terms: D000818:Animals; D054418:Chemokine CCL20 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D003920:Diabetes Mellitus / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007249:Inflammation / Q000235:genetics* / Q000473:pathology; D007333:Insulin Resistance / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008820:Mice, Obese; D016328:NF-kappa B / Q000235:genetics; D009765:Obesity / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D054399:Receptors, CCR6 / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D051996:Transcription Factor RelA / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism
chemical_list: C106311:CCR6 protein, human; D054418:Chemokine CCL20; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D016328:NF-kappa B; D054399:Receptors, CCR6; C498144:Rela protein, mouse; D051996:Transcription Factor RelA
keywords: Chemokine; Cytokine; Diabetes; Inflammation; Innate immunity; Transcription