Immune Sculpting of Norepinephrine on MHC-I, B7-1, IDO and B7-H1 Expression and Regulation of Proliferation and Invasion in Pancreatic Carcinoma Cells

Background: The sympathetic neurotransmitter Norepinephrine (NE) contributes to tumorigenesis and cancer progression. This study aims to investigate the role of NE in modulating the immune phenotype and allowing pancreatic carcinoma (PC) cells to escape the immune response. Methods: Varied concentrations of NE and interferon-gamma (IFN-gamma) were administrated to MIA PaCa-2 and BxPC-3 cell lines for 48 hours. Proliferation and invasion were then investigated using an MTT assay and a membrane invasion culture system respectively. MHC-I, B7-1, IDO and B7-H1 expression were measured using real-time quantitative RT-PCR, western blotting and immunocytochemistry. The synergistic and time-dependent effects of NE/IFN-gamma were also investigated. Adrenergic antagonists were used to identify the relevant target receptor of NE. Results: The results showed that NE had dose-dependent and time-dependent effects on cell biological processes as well as on the expression of MHC-I, B7-1, IDO and B7-H1. These effects occurred mainly via the beta(2)-adrenergic receptor. Long-term NE treatment was able to antagonize some of the effects of IFN-gamma (after 2 weeks of treatment), but NE and IFN-gamma had significant synergistic stimulatory effects on IDO and B7-H1 expression. The residual effects on biological activities lasted for 2 weeks, while the immunophenotypic changes decreased at early time points after treatment. Conclusions: NE plays important roles in modulating PC cell biological activities and affecting MHC-I, B7-1, IDO and B7-H1 expression in vitro, mainly via the beta 2-adrenergic receptor (beta 2-AR) in a time-and dose-dependent fashion. Only at extended treatment durations could NE affect PC cell progression and immune evasion.