Anti-inflammatory action of exendin-4 in human islets is enhanced by phosphodiesterase inhibitors: potential therapeutic benefits in diabetic patients

• Published in: Diabetologia Vol. 53; no. 11; pp. 2357 - 2368
• Main Authors: Pugazhenthi, U, Velmurugan, K, Tran, A, Mahaffey, G, Pugazhenthi, S
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Berlin/Heidelberg : Springer-Verlag 01.11.2010; Springer-Verlag; Springer; Springer Nature B.V
• Subjects: Analysis of Variance; Anti-inflammatory; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Biological and medical sciences; Blotting, Western; cAMP; Cell Line; Cells, Cultured; Chemokine CXCL10 - genetics; Chemokine CXCL10 - metabolism; CXCL10; Cyclic AMP - metabolism; Cyclic AMP - pharmacology; cytokines; diabetes; Diabetes Mellitus - drug therapy; Diabetes Mellitus - metabolism; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Enzyme-Linked Immunosorbent Assay; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Exenatide; Exendin-4; Human Physiology; Humans; In Vitro Techniques; Interferon-gamma - pharmacology; Interferon-γ; Interleukin-1beta - pharmacology; Internal Medicine; Islets of Langerhans - drug effects; Islets of Langerhans - metabolism; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; NF-kappa B; NF-kB; Peptides - pharmacology; Peptides - therapeutic use; Phosphodiesterase Inhibitors - pharmacology; Phosphodiesterase Inhibitors - therapeutic use; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction - drug effects; STAT-1; STAT1 Transcription Factor - metabolism; Tumor Necrosis Factor-alpha - pharmacology; Venoms - pharmacology; Venoms - therapeutic use; CXCL10; Cytokines; NF-kB; STAT-1; Interferon; Diabetes; cAMP; Anti-inflammatory; Exendin-4; Endocrinopathy; Human; Diabetes mellitus; Cytokine; Cyclic AMP; Interferon-γ; Gamma interferon
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-010-1849-y

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.