Norepinephrine-mediated inhibition of antitumor cytotoxic T lymphocyte generation involves a beta-adrenergic receptor mechanism and decreased TNF-alpha gene expression.
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.
Kalinichenko
V V
VV
Center for Molecular Biology of Oral Diseases, Department of Biochemistry and Molecular Biology, University of Illinois, Chicago 60612, USA.
Mokyr
M B
MB
Graf
L H
LH
Cohen
R L
RL
Chambers
D A
DA
D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis; D017252:CD3 Complex / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000235:genetics / Q000276:immunology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000276:immunology*; D007424:Intracellular Fluid / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D016131:Lymphocyte Subsets / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008558:Melphalan / Q000633:toxicity; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009638:Norepinephrine / Q000494:pharmacology*; D010954:Plasmacytoma / Q000139:chemically induced / Q000276:immunology; D011433:Propranolol / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D013154:Spleen / Q000276:immunology / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics* / Q000494:pharmacology
D000943:Antigens, Differentiation; D017252:CD3 Complex; D012333:RNA, Messenger; D011943:Receptors, Adrenergic, beta; D014409:Tumor Necrosis Factor-alpha; C036763:monocyte-macrophage differentiation antigen; D011433:Propranolol; D008558:Melphalan; D009638:Norepinephrine