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Blood, 1 October 2005, Vol. 106, No. 7, pp. 2409-2416.
Prepublished online as a Blood First Edition Paper on June 14, 2005; DOI 10.1182/blood-2005-03-0854.
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Submitted March 1, 2005
Accepted May 31, 2005
Triptolide, a constituent of immunosuppressive Chinese herbal medicine, is a potent suppressor of dendritic cell maturation and trafficking
Xin Chen*, Takaya Murakami, Joost J Oppenheim, and Zack Howard
Basic Research Program, SAIC-Frederick, Inc., Frederick, Maryland, USA
Laboratory of Molecular Immunoregulation, Center for Cancer research, National Cancer Institute, Frederick, Maryland, USA
* Corresponding author; email: xinc{at}mail.ncifcrf.gov.
Triptolide (TPT) is a chemically defined, potent immunosuppressive compound isolated from an anti-inflammatory Chinese herbal medicine. TPT has been reported to inhibit autoimmunity, allograft rejection and GVHD, and its efficacy was previously attributed to the suppression of T cells. Since dendritic cells (DCs) play a major role in the initiation of T cell-mediated immunity, we studied the effects of TPT on the phenotype, function and migration of human monocyte-derived DC. TPT-treatment, over a pharmacological concentration range, inhibited the LPS-induced phenotypic changes, characteristic of mature DC and the production of IL-12p70. Consequently the allostimulatory functions of DCs were impaired by TPT treatment. Furthermore, the calcium mobilization and chemotactic responses of LPS-stimulated-DC to SLC/CCL21 were significantly lower in TPT-treated than untreated DC, in association with lower CCR7 and higher CCR5 expression. Egress of Langerhans cells (LCs) from explanted mouse skin in response to MIP-3beta/CCL19 was arrested by TPT. In vivo administration of TPT markedly inhibited hapten (FITC)-stimulated migration of mouse skin LCs to the draining lymph nodes. These data provide new insight into the mechanism of action of TPT and indicate that the inhibition of maturation and trafficking of DC by TPT contributes to its immunosuppressive effects.
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