Experimental autoimmune encephalomyelitis (EAE), an animal model of
multiple sclerosis, is a Th1-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-specific recall responses and inhibition of the Th1-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 Th1
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 Th1-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 Th1-mediated inflammatory diseases.