title: Trp-P-1, a carcinogenic heterocyclic amine, inhibits lipopolysaccharide-induced maturation and activation of human dendritic cells.
abstract: Carcinogens frequently provoke immunosuppressive effects thereby allowing cancer cells to persist in the host. 3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) is a carcinogenic heterocyclic amine that is abundantly produced by overcooking meat and fish. Here, we investigated the effect of Trp-P-1 on dendritic cells (DCs), which play a central role in the appropriate activation of the host immune system. When human monocyte-derived DCs were stimulated with lipopolysaccharide (LPS), the DCs became mature with an increase in the expression of co-stimulatory receptors such as CD80, CD86, and MHC molecules and a decrease in phagocytic capacity. Trp-P-1 inhibited all of these phenomena under the same conditions. In addition, Trp-P-1 inhibited production of the cytokines TNF-α and IL-12 in LPS-stimulated DCs. Furthermore, DCs that were pre-exposed to Trp-P-1 were less efficient in inducing activation and proliferation of autologous T cells than control DCs. Trp-P-1 also attenuated the ability of DCs to directly kill T-cell lymphoma Jurkat cells. Mechanism studies showed that Trp-P-1 did not inhibit LPS-binding to Toll-like receptor 4 but interfered with the signaling pathways mediated through p38 kinase. In conclusion, our results suggest that Trp-P-1 is immunosuppressive by inhibiting the functionality of DCs that play an essential role in the appropriate induction of anti-cancer immune responses.
authors.affiliation: Department of Agricultural Biotechnology and Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Jun Ho
authors.initials: JH
authors.lastname: Jeon
authors.forename: Sun Kyung
authors.initials: SK
authors.lastname: Kim
authors.forename: Jintaek
authors.initials: J
authors.lastname: Im
authors.forename: Ki Bum
authors.initials: KB
authors.lastname: Ahn
authors.forename: Jung Eun
authors.initials: JE
authors.lastname: Baik
authors.forename: Ok-Jin
authors.initials: OJ
authors.lastname: Park
authors.forename: Cheol-Heui
authors.initials: CH
authors.lastname: Yun
authors.forename: Seung Hyun
authors.initials: SH
authors.lastname: Han
mesh_terms: D002243:Carbolines / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D006801:Humans; D018664:Interleukin-12 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects; D010587:Phagocytosis / Q000187:drug effects; D010766:Phosphorylation; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D002243:Carbolines; D002273:Carcinogens; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D048051:p38 Mitogen-Activated Protein Kinases; C019132:3-amino-1,4-dimethyl-5H-pyrido(4,3-b)indole