Glucagon-like peptide-1 receptor agonist exendin-4 mitigates lipopolysaccharide-induced inflammatory responses in RAW264.7 macrophages

Macrophages play a critical role in the immune response against pathogen invasion and injury. However, under pathological stress, macrophages could have aberrant roles and contribute to the pathogenesis of inflammatory associated diseases. Exenatide is a glucagon-like peptide 1(GLP-1) agonist, which belongs to the family of synthetic exendin-based incretin mimetic. Exendin related compounds reduce glucose levels in type 2 diabetes patients. The purpose of this study was to examine the anti-inflammatory effects of exendin-4 in LPS-induced activation of macrophages. We show that exendin-4 inhibits LPS-induced expression of inflammatory mediators (iNOS, COX-2, PGE2 and NO) and pro-inflammatory cytokines (TNF-alpha, IL-1 beta, and IL-6) in RAW264.7 macrophages. Exendin-4 pretreatment mitigates LPS induced cellular ROS production. Mechanistically, Exendin-4 suppresses the LPS-induced activation of the JNK and AP-1 pathway. Furthermore, exendin-4 suppresses both nuclear p65 accumulation and transfected NF-kappa B promoter activity, indicating it inhibits the activation of the NF-kappa B pathway. Our study demonstrates that the GLP-1 agonist exendin-4 has a potent and-inflammatory effect independent on its glucose reducing ability, and exendin-4 has the potential implication to treat inflammatory associated diseases.