Impairment of human dendritic cell function by a food-borne carcinogenic heterocyclic aromatic amine, 3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (89.38)

Abstract

Abstract Carcinogens frequently provoke immunosuppressive effects and thereby cancer cells are not easily removed by host immune system having carcinogen(s). Heterocyclic amines (HCA) such as 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1), 2-amino-1-methyl-6 phenylimidazo[4,5-b]pyridine (PhIP), and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), are dietary carcinogens that are abundantly produced by overcooking meat and fish. Here, we investigated the effect of HCA on the activation of dendritic cells (DCs) which play an important role in the initiation of immune responses. When human monocyte-derived DCs were stimulated with lipopolysaccharide (LPS), DCs became mature with an increase in the expression of co-stimulatory receptors such as CD80 and CD86, and MHC molecules but a decrease in the phagocytic capacity. However, Trp-P-1 but not PhIP or IQ alleviated all of these phenomena under the same condition. In addition, Trp-P-1 inhibited the production of cytokines, TNF-α and IL-12, by LPS-stimulated DCs. Furthermore, DCs pre-exposed to Trp-P-1 were less efficient in the activation and proliferation of autologous T cells than the control DCs. The suppressive effect of Trp-P-1 on the LPS-induced DC activation appears to be due to interference with the interaction between LPS and DCs as determined by a binding assay using FITC-labeled LPS. Conclusively, these results suggest that Trp-P-1 impairs the function of DCs for the appropriate induction of immune responses.