1. Nicotine up-regulated 4-1BBL expression by activating Mek-PI3K pathway augments the efficacy of bone marrow-derived dendritic cell vaccination.
- Author
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Jin HJ, Sui HX, Wang YN, and Gao FG
- Subjects
- 4-1BB Ligand genetics, Adjuvants, Immunologic administration & dosage, Adjuvants, Immunologic therapeutic use, Animals, Bone Marrow Transplantation methods, Cancer Vaccines administration & dosage, Cancer Vaccines therapeutic use, Cell Line, Cells, Cultured, Coculture Techniques, Female, Gene Expression Regulation, Neoplastic immunology, MAP Kinase Kinase Kinases physiology, MAP Kinase Signaling System drug effects, MAP Kinase Signaling System immunology, Mice, Mice, Inbred C57BL, Tumor Cells, Cultured, Up-Regulation immunology, 4-1BB Ligand biosynthesis, Bone Marrow Transplantation immunology, Cancer Vaccines immunology, Dendritic Cells transplantation, Gene Expression Regulation, Neoplastic drug effects, MAP Kinase Kinase Kinases metabolism, Nicotine pharmacology, Phosphatidylinositol 3-Kinase physiology
- Abstract
Purpose: To explore the role of 4-1BBL in nicotine-treated immature dendritic cells (imDCs) mediated anti-tumor effects., Methods: Bone marrow-derived imDCs were stimulated with nicotine and 4-1BBL expression was determinated by flow cytometry, Western blot and RT-PCR respectively. Then, the roles of 4-1BBL in nicotine-augmented DCs-dependent T cell proliferation, CTL priming and anti-tumor effects were investigated by BrdU cell proliferation assay, enzyme-linked immunospot assay and in vivo preventive effect on tumor development, respectively. Finally, using relative kinase inhibitors, the mechanism of 4-1BBL up-regulation by nicotine stimulation and the roles of Mek-PI3K signal pathways in nicotine-augmented DCs-dependent T cell proliferation were explored by Western blot and BrdU cell proliferation assay, respectively., Results: Firstly, nicotine could up-regulate 4-1BBL expression in both protein and mRNA levels. Secondly, the effects of nicotine-augmented DCs-dependent T-cell proliferation, CTL priming and anti-tumor effects could be significantly abolished by blocking CD80, CD86 and 4-1BBL activity, respectively. Thirdly, the combined blockages of CD80/CD86, CD80/4-1BBL, CD86/4-1BBL or CD80/CD86/4-1BBL signals could decrease 53.2 %, 29.6 %, 27.9 % and 54.5 % nicotine-enhanced T cell proliferation, respectively. Importantly, nicotine-induced 4-1BBL up-regulation could be decreased by the usage of Mek-PI3K pathway kinase inhibitors. The pre-treatment of Mek-p38-PI3K kinase inhibitors could obviously abolish nicotine-augmented DCs-dependent T cell proliferation., Conclusions: CD80/CD86 and 4-1BBL are critical for nicotine augmented DCs-mediated anti-tumor effects. 4-1BBL and CD80/CD86 could be considered as potential candidates for preventive and therapeutic tumor vaccination.
- Published
- 2013
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