IL-1β reciprocally regulates chemokine and insulin secretion in pancreatic β-cells via NF-κB

Am J Physiol Endocrinol Metab. 2015 Oct 15;309(8):E715-26. doi: 10.1152/ajpendo.00153.2015. Epub 2015 Aug 25.


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.

Keywords: chemokine; inflammation; insulin secretion; interleukin-1; nitric oxide.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Chemokine CCL2 / genetics
  • Chemokine CCL2 / metabolism
  • Chemokine CCL20 / genetics
  • Chemokine CCL20 / metabolism
  • Chemokines / genetics
  • Chemokines / metabolism*
  • Diabetes Mellitus / metabolism*
  • Electron Spin Resonance Spectroscopy
  • Enzyme-Linked Immunosorbent Assay
  • Gene Expression Regulation
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Immunoblotting
  • Insulin / genetics
  • Insulin / metabolism*
  • Insulin Secretion
  • Insulin-Secreting Cells / metabolism*
  • Insulinoma
  • Interleukin-1beta / metabolism*
  • NF-kappa B / metabolism*
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase Type II / genetics
  • Nitric Oxide Synthase Type II / metabolism
  • Oxygen Consumption
  • Pancreatic Neoplasms
  • Patch-Clamp Techniques
  • RNA, Messenger / metabolism*
  • Rats
  • Rats, Wistar
  • Rats, Zucker
  • Reverse Transcriptase Polymerase Chain Reaction
  • Ribosomal Protein S9
  • Ribosomal Proteins / genetics
  • Ribosomal Proteins / metabolism
  • Tumor Cells, Cultured


  • Ccl2 protein, rat
  • Ccl20 protein, rat
  • Chemokine CCL2
  • Chemokine CCL20
  • Chemokines
  • Homeodomain Proteins
  • IL1B protein, rat
  • Insulin
  • Interleukin-1beta
  • NF-kappa B
  • Nkx6-1 protein, rat
  • RNA, Messenger
  • Ribosomal Protein S9
  • Ribosomal Proteins
  • Nitric Oxide
  • Nitric Oxide Synthase Type II
  • Nos2 protein, rat