title: IL-1β reciprocally regulates chemokine and insulin secretion in pancreatic β-cells via NF-κB.
abstract: Proinflammatory cytokines impact islet β-cell mass and function by altering the transcriptional activity within pancreatic β-cells, producing increases in intracellular nitric oxide abundance and the synthesis and secretion of immunomodulatory proteins such as chemokines. Herein, we report that IL-1β, a major mediator of inflammatory responses associated with diabetes development, coordinately and reciprocally regulates chemokine and insulin secretion. We discovered that NF-κB controls the increase in chemokine transcription and secretion as well as the decrease in both insulin secretion and proliferation in response to IL-1β. Nitric oxide production, which is markedly elevated in pancreatic β-cells exposed to IL-1β, is a negative regulator of both glucose-stimulated insulin secretion and glucose-induced increases in intracellular calcium levels. By contrast, the IL-1β-mediated production of the chemokines CCL2 and CCL20 was not influenced by either nitric oxide levels or glucose concentration. Instead, the synthesis and secretion of CCL2 and CCL20 in response to IL-1β were dependent on NF-κB transcriptional activity. We conclude that IL-1β-induced transcriptional reprogramming via NF-κB reciprocally regulates chemokine and insulin secretion while also negatively regulating β-cell proliferation. These findings are consistent with NF-κB as a major regulatory node controlling inflammation-associated alterations in islet β-cell function and mass.
authors: Laboratory of Islet Biology and Inflammation, Pennington Biomedical Research Center, Baton Rouge, Louisiana;
authors: Susan J
authors: SJ
authors: Burke
authors: Laboratory of Oxidative Stress and Disease, Pennington Biomedical Research Center, Baton Rouge, Louisiana;
authors: Krisztian
authors: K
authors: Stadler
authors: Duke Molecular Physiology Institute, Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, North Carolina;
authors: Danhong
authors: D
authors: Lu
authors: Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana;
authors: Evanna
authors: E
authors: Gleason
authors: Department of Nutrition, University of Tennessee, Knoxville, Knoxville, Tennessee;
authors: Anna
authors: A
authors: Han
authors: Department of Nutrition, University of Tennessee, Knoxville, Knoxville, Tennessee;
authors: Dallas R
authors: DR
authors: Donohoe
authors: Laboratory of Autonomic Neuroscience, Pennington Biomedical Research Center, Baton Rouge, Louisiana; and.
authors: Richard C
authors: RC
authors: Rogers
authors: Laboratory of Autonomic Neuroscience, Pennington Biomedical Research Center, Baton Rouge, Louisiana; and.
authors: Gerlinda E
authors: GE
authors: Hermann
authors: Department of Surgery, Graduate School of Medicine, University of Tennessee Medical Center, Knoxville, Tennessee.
authors: Michael D
authors: MD
authors: Karlstad
authors: Laboratory of Islet Biology and Inflammation, Pennington Biomedical Research Center, Baton Rouge, Louisiana; Jason.collier@pbrc.edu.
authors: J Jason
authors: JJ
authors: Collier
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D054418:Chemokine CCL20 / Q000235:genetics / Q000378:metabolism; D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000378:metabolism*; D004578:Electron Spin Resonance Spectroscopy; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D015151:Immunoblotting; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007340:Insulinoma; D053583:Interleukin-1beta / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D010101:Oxygen Consumption; D010190:Pancreatic Neoplasms; D018408:Patch-Clamp Techniques; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011924:Rats, Zucker; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000091243:Ribosomal Protein S9; D012269:Ribosomal Proteins / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: C491766:Ccl2 protein, rat; C486997:Ccl20 protein, rat; D018932:Chemokine CCL2; D054418:Chemokine CCL20; D018925:Chemokines; D018398:Homeodomain Proteins; C000594089:IL1B protein, rat; D007328:Insulin; D053583:Interleukin-1beta; D016328:NF-kappa B; C491327:Nkx6-1 protein, rat; D012333:RNA, Messenger; D000091243:Ribosomal Protein S9; D012269:Ribosomal Proteins; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat
keywords: chemokine; inflammation; insulin secretion; interleukin-1; nitric oxide