These effects are lost completely when the interaction of GXM with FcγRIIB is blocked [17]. Moreover, we have demonstrated previously the capacity of GXM to dampen the immune response in an experimental model of collagen-induced arthritis [14], an effect that possibly occurs upon engagement of FcγRIIB [38]. FcγRIIB engagement by GXM, with consequent SHIP activation, appears to be a critical event that produces anti-inflammatory effects by blocking nuclear factor κB (NFκB) activation [14]. Moreover, it has been reported

that FcγRIIB is a regulator of apoptosis [39]. In this paper, for the first time, we provide evidence that FcγRIIB is involved in the up-regulation of FasL, with consequent induction of apoptosis. In particular, we demonstrate that the mechanism controlling FasL up-regulation is ascribed principally to GXM/FcγRIIB interaction

and is mediated by activation of JNK, p38 and c-Jun. JNK and p38 are activated independently, LY2157299 mouse but both induce c-Jun activation. In addition, activation of c-Jun is regulated by FcγRIIB; therefore, FasL overexpression is dependent, at least in part, on c-Jun activation. These observations are supported by recent studies showing that FcγRIIB engagement induces phosphorylation of the pro-apoptotic molecule JNK [40]. However, no evidence has yet been provided that FcγRIIB selleck products is involved in regulation of FasL expression. The processes that regulate FasL up-regulation were, in fact, largely unknown. Here we report for the first time that there is a direct relationship between FcγRIIB and FasL regulation. Indeed, a proteolytic release of FasL from the cellular membrane has already been documented [41],

thus the possibility arises that soluble FasL could be generated during GXM stimulation. The shedding of FasL could account for the relative difficulty in detecting a strong increase in the percentage of FasL-positive cells.We cannot exclude the possibility that additional cellular receptors such as TLR-2, TLR-4, CD14 and CD18, which are exploited by GXM, might participate in the activation of JNK and p38 and, as a consequence, may also contribute to FasL up-regulation. This is conceivable for three reasons. Chlormezanone First, an involvement of TLR in JNK and p38 phosphorylation has been reported [42,43]. Secondly, activation of JNK and p38 is crucial for the up-regulation of FasL, as demonstrated by the effect of pharmacological inhibitors of both JNK and p38 MAPK. Finally, we have demonstrated previously that multiple receptors such as TLR-4, CD14 and CD18 are possibly involved in GXM-mediated FasL up-regulation [12]. Therefore, it is conceivable that the signal pathway that involves Myd88 with consequent activation of p38 and c-Jun contributes to up-regulation of FasL. In this paper, however, it is reported that FcγRII did not seem to be involved in this phenomenon [12]. This apparent discrepancy is due probably to the use of different experimental conditions.