Abstract
We have previously shown that norepinephrine (NE) inhibits the in vitro generation of anti-MOPC-315 CTL activity by spleen cells from BALB/c mice rejecting a large MOPC-315 tumor as a consequence of low-dose melphalan (l -phenylalanine mustard (l -PAM)) treatment (l -PAM TuB spleen cells). Since TNF-alpha plays a key role in the generation of antitumor CTL activity in this system, we determined whether NE mediates this inhibition through inhibition of TNF-alpha production. Here, we show that NE inhibits the production of TNF-alpha protein and mRNA by l -PAM TuB spleen cells stimulated in vitro with mitomycin C-treated tumor cells. Flow cytometric analysis of intracellular expression of TNF-alpha revealed substantial NE-mediated decreases in the percentages of TNF-alpha+ cells among CD4+ and CD8+ T cells and F4/80+ activated macrophages. NE inhibition of CTL generation was largely overcome by addition of TNF-alpha to the stimulation cultures. When the beta-adrenergic antagonist propranolol was added to the stimulation cultures of l -PAM TuB spleen cells at a concentration that prevented NE-induced cAMP elevation, the NE-mediated decrease in TNF-alpha mRNA and NE-mediated inhibition of CTL generation were reversed. Collectively, these results suggest that NE inhibits antitumor CTL generation, at least in part, by inhibiting TNF-alpha synthesis through a mechanism(s) involving beta-adrenergic receptor signaling.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antigens, Differentiation / biosynthesis
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CD3 Complex / biosynthesis
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CD4-Positive T-Lymphocytes / metabolism
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CD8-Positive T-Lymphocytes / metabolism
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Cytotoxicity, Immunologic / genetics
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Cytotoxicity, Immunologic / immunology*
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Female
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Gene Expression Regulation, Neoplastic / drug effects
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Gene Expression Regulation, Neoplastic / immunology*
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Intracellular Fluid / drug effects
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Intracellular Fluid / immunology
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Intracellular Fluid / metabolism
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Lymphocyte Activation / genetics
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Lymphocyte Activation / immunology*
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Lymphocyte Subsets / metabolism
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Macrophages / drug effects
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Macrophages / metabolism
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Melphalan / toxicity
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Mice
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Mice, Inbred BALB C
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Neoplasm Transplantation
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Norepinephrine / pharmacology*
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Plasmacytoma / chemically induced
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Plasmacytoma / immunology
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Propranolol / pharmacology
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RNA, Messenger / biosynthesis
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RNA, Messenger / drug effects
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Receptors, Adrenergic, beta / physiology*
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Spleen / immunology
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Spleen / pathology
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T-Lymphocytes, Cytotoxic / immunology*
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Tumor Cells, Cultured
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
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Tumor Necrosis Factor-alpha / biosynthesis
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Tumor Necrosis Factor-alpha / genetics*
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Tumor Necrosis Factor-alpha / pharmacology
Substances
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Antigens, Differentiation
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CD3 Complex
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RNA, Messenger
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Receptors, Adrenergic, beta
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Tumor Necrosis Factor-alpha
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monocyte-macrophage differentiation antigen
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Propranolol
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Melphalan
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Norepinephrine