Anti-inflammatory Action of exendin-4 in Human Islets Is Enhanced by Phosphodiesterase Inhibitors: Potential Therapeutic Benefits in Diabetic Patients

Diabetologia. 2010 Nov;53(11):2357-68. doi: 10.1007/s00125-010-1849-y. Epub 2010 Jul 16.

Abstract

Aims/hypothesis: Exendin-4, a glucagon-like peptide-1 (GLP-1) analogue, is reported to have modest anti-inflammatory effects in addition to that of improving beta cell survival. We therefore sought to determine whether exendin-4 decreases expression of the gene encoding chemokine (C-X-C motif) ligand (CXCL)10, which plays a role in initiating insulitis in type 1 diabetes.

Methods: The expression of CXCL10 in human islets was determined at the mRNA level by real-time RT-PCR analysis and at the protein level by western blotting. The level of CXCL10 in culture medium was measured by ELISA. Pathway-specific gene expression profiling was carried out to determine the expression of a panel of genes encoding chemokines and cytokines in human islets exposed to cytokines.

Results: IFN-γ induced expression of CXCL10 through activation of signal transducer and activator of transcription-1 (STAT-1). A combination of cytokines (IL-1β, TNF-α and IFN-γ) showed strong synergy in the induction of numerous chemokines and cytokines through nuclear factor kappa B and STAT-1. Exendin-4 suppressed basal expression of several inflammatory mediators. In combination with phosphodiesterase inhibitors, exendin-4 also decreased IFN-γ-induced CXCL10 expression in human islets and in MIN6 cells (a mouse beta cell line), and its secretion into the culture medium. Exendin-4 action was mimicked by forskolin, an activator of adenylyl cyclase, and by dibutyryl cyclic AMP. Protein kinase A was not involved in mediating exendin-4 action on CXCL10. The mechanism of exendin-4's anti-inflammatory action involved decreases in STAT-1 levels.

Conclusions/interpretation: These findings suggest that the GLP-1-cyclic AMP pathway decreases islet inflammation in addition to its known effects on beta cell survival.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Anti-Inflammatory Agents / pharmacology*
  • Anti-Inflammatory Agents / therapeutic use
  • Blotting, Western
  • Cell Line
  • Cells, Cultured
  • Chemokine CXCL10 / genetics
  • Chemokine CXCL10 / metabolism
  • Cyclic AMP / metabolism
  • Cyclic AMP / pharmacology
  • Diabetes Mellitus / drug therapy*
  • Diabetes Mellitus / metabolism
  • Enzyme-Linked Immunosorbent Assay
  • Exenatide
  • Humans
  • In Vitro Techniques
  • Interferon-gamma / pharmacology
  • Interleukin-1beta / pharmacology
  • Islets of Langerhans / drug effects*
  • Islets of Langerhans / metabolism*
  • NF-kappa B
  • Peptides / pharmacology*
  • Peptides / therapeutic use
  • Phosphodiesterase Inhibitors / pharmacology*
  • Phosphodiesterase Inhibitors / therapeutic use
  • RNA, Messenger
  • Reverse Transcriptase Polymerase Chain Reaction
  • STAT1 Transcription Factor / metabolism
  • Signal Transduction / drug effects
  • Tumor Necrosis Factor-alpha / pharmacology
  • Venoms / pharmacology*
  • Venoms / therapeutic use

Substances

  • Anti-Inflammatory Agents
  • CXCL10 protein, human
  • Chemokine CXCL10
  • Interleukin-1beta
  • NF-kappa B
  • Peptides
  • Phosphodiesterase Inhibitors
  • RNA, Messenger
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Tumor Necrosis Factor-alpha
  • Venoms
  • Interferon-gamma
  • Exenatide
  • Cyclic AMP