Immunosuppressant Sinomenine Promotes Differentiation of Bone Marrow Progenitors to IL-10-Producing Ia^low Regulatory Dendritic Cells Leading to the Prolongation of Allograft Survival.

Sinomenine (SN), an immunosuppressive compound derived from the Chinese medicinal plant Sinomenium acutum, effectively inhibits both proinflammatory factor production and lymphocyte proliferation. However, the effects of SN on dendritic cells (DC), the professional antigen-presenting cells, have not been elucidated. In this study, we examined the effects of SN on DC generation, maturation and function. We found that SN affected DC in a dose dependent manner; significantly inhibiting surface expression of MHC class II, CD86, and CD40, production of IL-12, TNF-a, IL-1b, and T cell-allostimulatory activity. SN targets antigen-presenting capacity of DC not only via the MHC class II pathway, but also impairs DC migration by inhibiting LPS-induced up-regulation of CCR7 and CXCR4 expression. These inhibitory effects on DC may be partially due to SN-mediated suppression of NF-kB and p38 MAPK pathways. Further study showed that SN-treated DC (DC-SN) induce donor-specific T cell hyporesponsiveness and trigger generation of IL-10-producing T regulatory-like cells in vitro. In vivo transplant studies revealed that, compared to pretreatment with immature DC, pretreatment of recipients with DC-SN could significantly prolong allograft survival, although long-term allograft acceptance was not achieved. Importantly, pretreatment of recipients with DC-SN in combination with SN administration profoundly prolonged allograft survival, resulting in long-term survival of 30% of allografts. Increased generation of CD4⁺CD25⁺ Treg cells and enhanced microchimerism in recipients brought on by combination treatment may contribute to this extension of allograft lifespan. Our results demonstrate that SN can promote bone marrow progenitors differentiation to IL-10-producing (Ia^low) regulatory DC which contribute to induction of tolerance by increase generation of Treg cells.