5-Aminoimidazole-4-Carboxamide Ribonucleoside:A Novel Immunomodulator with Therapeutic Efficacy in Experimental Autoimmune Encephalomyelitis

摘要

Experimental autoimmune encephalomyelitis (EAE),an animal model of multiple sclerosis,is a Thl-mediated inflammatory demyelinating disease of the CNS.AMP-activated protein kinase was reported recently to have anti-inflammatory activities by negatively regulating NF-kappaB signaling.In this study,we investigated the prophylactic and therapeutic efficacy of an AMP-activated protein kinase activator,5-aminoimidazole-4-carboxamide ribonucleoside (AICAR),in active and passive EAE induced by active immunization with PLP_(139-151) or MOG_(35-55) and in adoptive transfer of PLP_(139-151)-sensitized T cells,respectively.In vivo treatment with AICAR exerted both prophylactic and therapeutic effects on EAE,attenuating the severity of clinical disease.The anti-inflammatory effects of AICAR were associated with the inhibition of the Ag-speciflc recall responses and inhibition of the Thl-type cytokines IFN-gamma and TNF-alpha,whereas it induced the production of Th2 cytokines IL-4 and IL-10.Treatment of PLP_(139-151)-specific T cells in vitro with AICAR decreased their expression of T-bet in response to IL-12,a Thl transcription factor,whereas in response to IL-4,it induced the expression and phosphorylation of Th2 transcription factors GATA3 and STAT6,respectively.Moreover,treatment of APCs in vitro with AICAR inhibited their capability to present the proteolipid protein peptide to PLP_(139-151)-specifIc T cells.In an irrelevant Thl-mediated,OT-2 TCR transgenic mouse model,AICAR impaired in vivo Ag-specific expansion of CD4~+ T cells.Together,these findings show for the first time that AICAR is a novel immunomodulator with promising beneficial effects for the treatment of multiple sclerosis and other Thl-mediated inflammatory diseases.