KBxN mice spontaneously develop arthritis similar to RA in humans, and transfer of serum from arthritic K/BxN mice into healthy animals provokes arthritis within days independently on T and B cells. K/BxN serum-induced arthritis is mediated by anti-glucose-6-phsophate-isomerase IgGs. Here we demonstrate that synthetic glycolipid ligand, a-galactocylceramide (alpha-GalCer) or its analogue with an elongated sphingosine chain strongly suppressed K/BxN serum transfer arthritis by inhibiting inflammatory cellular infiltration and subsequent destruction of cartilage and bone. The inhibitory effect mediated by these glycolipd ligands was abolished by neutralization of IFN-gamma and systemic administration of IFN-gamma prevented the development of inflammatory arthritis. Furthermore, we demonstrate that histamine release involved in the induction of arthritis was suppressed by administration of glycolipid ligands or IFN-gamma. In addition, degranulation of mast cells in synomium was significantly suppressed in glycolipid ligands-treated mice, suggesting that the suppression of mast cell activation contributes to the inhibition of arthritis.