Second, PGE2 could not directly inhibit DC maturation by itself. We found that IC not only induced considerable amount of PGE2 release from FcγRIIb−/− DCs, but also promoted the maturation of FcγRIIb−/− DCs, indicating

that PGE2 alone could not inhibit DC maturation. In addition, PGE2 inhibitor, celecoxib, could not completely restore the downregulated expression click here of costimulatory molecules such as CD40, CD80 and CD86 and MHC class II (I-Ab) on IC-pretreated TLR-triggered DCs (data not shown). Several other investigations have presented inconsistent observations about the effect of PGE2 on the maturation of DCs. Some studies have provided evidence that PGE2 enhances the maturation of DCs by inducing costimulatory molecules and IL-12 33, 34; however, other studies have provided evidence that PGE2 from saliva of blood-sucking arthropods is a strong inhibitor of DCs maturation

35. Third, the DC-initiated T-cell proliferation that we observed above was the net consequence of the interplay between FcγRIIb−/− DC-mediated activating signals and PGE-mediated direct inhibitory signals. In the case of IC pretreatment PF-02341066 supplier of FcγRIIb−/− DCs, FcγRIIb−/− DCs were more mature because activating signals were dominant, whereas PGE2 production was reduced because of deficiency of one type of FcγR(IIb). Therefore, IC pretreatment could not significantly inhibit LPS-stimulated FcγRIIb−/− DCs to induce T-cell responses. Artificial overexpression of FcγRIIb

not only enhances PGE2 production but also may polarize IC-triggered activating signal to inhibitory signal in DCs with increased tolerogenecity. To investigate the mechanisms underlying the regulatory effect of IC pretreatment, we had also detected whether other inhibitory cytokines, such as IL-10 and TGF-β, could be produced from DC-FcγRIIb after ligation by IC. However, no increase in IL-10 oxyclozanide and TGF-β can be detected, suggesting that IL-10 and TGF-β were not involved in attenuating progression of lupus by DC-FcγRIIb. Although tolerogenic DCs and PGE2 have been reported to promote Treg development 30, we found that the frequency and regulatory function of Foxp3+ Tregs remained almost unchanged in MRL/lpr lupus mice after infusion of DC-FcγRIIb (data not shown), thus excluding the possibility that the regulatory role of DC-FcγRIIb was due to the induction of Foxp3+ Treg generation. In summary, our findings demonstrate that genetic modification of FcγRIIb can maintain the immature status and enhance tolerogenecity of DCs in the presence of IC. Infusion of DC-FcγRIIb can significantly attenuate T-cell response in MRL/lpr mice, leading to dampened progression of lupus.