Up-regulation of IL-10 expression in dendritic cells is involved in Trichosanthin-induced immunosuppression

We report here that Trichosanthin (Tk), a primary active component isolated from a Chinese traditional medicinal herb, Trichosanthes kirilowii, potently inhibits lymphocyte proliferative response in vitro. We found that Tk treatment increased production of the interleukins IL-4 and IL-10, while production of IL-2 and interferon-γ (IFN-γ) decreased in the allogeneic antigen-induced immune response. Moreover, up-regulation of IL-10 and IL-4 contributed to the inhibitory activities of Tk. Tk induced immunosuppression through an antigen presenting cell dependent way. Dendritic cells (DCs) are the most potent of the antigen presenting cells, which play a critical role in initiation and regulation of immune responses. We found that Tk could stimulate bone marrow-derived dendritic cells (BMDC) to express IL-10. In addition, pre-exposure of BMDC to Tk produced increased levels of IL-10, but decreased levels of IL-12, following subsequent lipopolysaccharide (LPS) stimulation. Using BMDC obtained from IL-10 deficient mice, we provided evidence that it was IL-10 derived from DCs that initiated the Tk-induced immunosuppression. Furthermore, we found that Tk activated c-Jun N-terminal kinase (JNK) of BMDC and that JNK and p38 mitogen-activated protein kinase (MAPK) activations were associated with Tk-induced IL-10 up-regulation. These data suggest that Tk acts on the function of DCs to change the ratio of IL-10 to IL-12 production and, thus, predominantly inhibits Th1 responses.