Agonist for G-proteini coupled receptor 131 attenuate systemic inflammatory syndrome
S.Y. Seong
Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul 110-799, Korea
Abstract:
The incidence of sepsis have steadily increased during the last few decades. The development of targeted therapy has been hampered due to multiple pathways activated by LPS in vivo. Here, we tested bioemulsifiers inhibiting interaction of LPS with Toll-like receptor 4 in vitro and in experimental mouse models. In addition to emulsification of LPS, the compounds activated G-protein coupled receptor 131 pathways and suppresed inflammation. We found that glycine-conjugated cholic acids (CCA) and taurine-CCA reduced LPS-mediated NF-kB activation. CCAs were also able to inhibit expression of costimulatory molecules, production of inflammatory cytokines and NO of dendritic cells (DCs) by LPS. In vivo, CCA administration reduced blood proinflammatory cytokines and improved mice survival following LPS challenge or in CLP (cecal ligation and puncture) model. They also prevented apoptosis of lymphocytes and dramatically increased myeloid-derived suppressor cell populations in vivo. CCA herein showed toxicity in animal models when used 100 times higher than effective dose. Taken together, CCA might mitigate the development of severe sepsis in patients.
