Abstract
Protosappanin A (PrA), an immunosuppressive ingredient of the medicinal herb Caesalpinia sappan L, prolongs heart allograft survival in rats, possibly by impairing the function of antigen-presenting cells (APCs). We examined the effects of PrA on the maturation and function of dendritic cells (DCs), a potent class of APCs, and the downstream cell–cell and intracellular signaling pathways mediating the immunosuppressive activity of PrA. PrA inhibited LPS-stimulated maturation of Wistar rat DCs in vitro as reflected by reduced expression of costimulatory molecules (CD80 and CD86) and reduced expression of TLR4 and NF-κB, two critical signaling components for antigen recognition. PrA also enhanced the release of IL-10 and decreased the release of IL-12 from DCs, but had no effect on the production of TGF-ß. In mixed cultures, Wistar DCs pretreated with PrA impaired the proliferation of Sprague Dawley (SD) rat T cells while promoting the expansion of SD rat CD4+CD25+ regulatory T cells (Tregs). Both oral PrA treatment and infusion of PrA-pretreated Wistar DCs prolonged cardiac allograft survival (Wistar donor, SD recipient) and expanded recipient CD4+CD25+Foxp3+ Tregs. Donor spleen cells, but not spleen cells from a third rat strain (DA), supported the expansion of recipient CD4+CD25+Foxp3+ Tregs and suppressed recipient T cell proliferation. We conclude that PrA triggers a tolerogenic state in DCs that allows for the induction of alloantigen-specific Tregs and the suppression of allograft rejection in vivo.
Highlights
Protosappanin A (PrA), a potent immunosuppressive agent derived from the traditional medicinal herb Caesalpinia sappan L, prolonged the survival of heart allografts in rat and prevented immune-mediated tissue damage [1,2]
We investigated whether Dendritic cells (DCs) treated with PrA still expressed these surface markers after activation by LPS
DCs cultured with the cytokines GM-CSF and IL-4 for 6 days were stimulated with LPS alone (10 ng/ml) or LPS plus PrA and cultured for an additional 48 h
Summary
Protosappanin A (PrA), a potent immunosuppressive agent derived from the traditional medicinal herb Caesalpinia sappan L, prolonged the survival of heart allografts in rat and prevented immune-mediated tissue damage [1,2]. Inhibition of acute tissue rejection was associated with reduced proliferation of recipient T cells and underexpression of NF-kB in infiltrating monocytes [3], but little is known of the intercellular and molecular signaling mechanisms for PrA-mediated immunosuppression. We examined the effect of PrA on DC phenotype and compared the effects of native and PrA-treated DCs on the proliferation and phenotype of T cells to elucidate the signaling mechanisms of PrA-mediated immunosuppresion. PrA administration or transfer of PrA-treated donor DCs led to recipient T cell hyporesponsiveness and Treg expansion as well as suppression of allograft rejection in a rat model of heart transplantation. This study identifies the probable mechanisms for the immunosuppressive effect of PrA
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