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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: OBJECTIVE, METHODS, RESULTS. Meshes: Analysis of Variance, Anti-Inflammatory Agents, Blotting, Western, Cell Line, Cells, Cultured, Chemokine CXCL10, Cyclic AMP, Diabetes Mellitus, Enzyme-Linked Immunosorbent Assay, Exenatide, Humans, In Vitro Techniques, Interferon-gamma, Interleukin-1beta, Islets of Langerhans, NF-kappa B, Peptides, Phosphodiesterase Inhibitors, RNA, Messenger, Reverse Transcriptase Polymerase Chain Reaction, STAT1 Transcription Factor, Signal Transduction, Tumor Necrosis Factor-alpha, Venoms.
user
Is anti-inflammatory action of exendin-4 in human islets enhanced by phosphodiesterase inhibitors : potential therapeutic benefits in diabetic patients? Context: 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. 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. 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.
assistant
These findings suggest that the GLP-1-cyclic AMP pathway decreases islet inflammation in addition to its known effects on beta cell survival. Final Decision: yes