title: Triptolide, a constituent of immunosuppressive Chinese herbal medicine, is a potent suppressor of dendritic-cell maturation and trafficking.
abstract: 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 graft-versus-host disease (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 DCs. TPT treatment, over a pharmacologic concentration range, inhibited the lipopolysaccharide (LPS)-induced phenotypic changes, characteristic of mature DCs and the production of interleukin-12p70 (IL-12p70). Consequently, the allostimulatory functions of DCs were impaired by TPT treatment. Furthermore, the calcium mobilization and chemotactic responses of LPS-stimulated DCs to secondary lymphoid tissue chemokine (SLC)/CC chemokine ligand 21 (CCL21) were significantly lower in TPT-treated than untreated DCs, in association with lower chemokine receptor 7 (CCR7) and higher CCR5 expression. Egress of Langerhans cells (LCs) from explanted mouse skin in response to macrophage inflammatory protein-3beta (MIP-3beta)/CCL19 was arrested by TPT. In vivo administration of TPT markedly inhibited hapten (fluorescein isothiocyanate [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 DCs by TPT contributes to its immunosuppressive effects.
authors.affiliation: Basic Research Program, Science Applications International Corporation-Frederick, Inc., Laboratory of Molecular Immunoregulation, National Cancer Institute-Frederick, Frederick, MD 21702-1201, USA. xinc@mail.ncifcrf.gov
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.forename: Takaya
authors.initials: T
authors.lastname: Murakami
authors.forename: Joost J
authors.initials: JJ
authors.lastname: Oppenheim
authors.forename: O M Zack
authors.initials: OM
authors.lastname: Howard
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis; D015551:Autoimmunity; D017252:CD3 Complex / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation; D002465:Cell Movement; D002469:Cell Separation; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D019742:Chemokines, CC / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology*; D004224:Diterpenes / Q000737:chemistry* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D004817:Epidermis / Q000378:metabolism; D004852:Epoxy Compounds; D005260:Female; D005434:Flow Cytometry; D016650:Fluorescein-5-isothiocyanate / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D018664:Interleukin-12 / Q000378:metabolism; D007801:Langerhans Cells / Q000166:cytology; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008070:Lipopolysaccharides / Q000378:metabolism; D008198:Lymph Nodes / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D010616:Phenanthrenes / Q000737:chemistry* / Q000494:pharmacology*; D010641:Phenotype; D021122:Protein Subunits / Q000378:metabolism; D019713:Receptors, CCR5 / Q000378:metabolism; D012867:Skin / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C515460:CCL19 protein, human; C515478:CCL21 protein, human; D017252:CD3 Complex; C515461:Ccl19 protein, mouse; C515479:Ccl21c protein, mouse; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D019742:Chemokines, CC; D016207:Cytokines; D004224:Diterpenes; D004365:Drugs, Chinese Herbal; D004852:Epoxy Compounds; D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D010616:Phenanthrenes; D021122:Protein Subunits; D019713:Receptors, CCR5; D018664:Interleukin-12; C001899:triptolide; D016650:Fluorescein-5-isothiocyanate; D002118:Calcium