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Neurotransmitter suppression of the in vitro generation of a cytotoxic T lymphocyte response against the syngeneic MOPC-315 plasmacytoma

  • Original Article
  • Catecholamine, CTL, Low-Dose Chemotherapy
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Abstract

We have previously shown that, as a consequence of low-dose melphalan (l-phenylalanine mustard (l-PAM) therapy, the hitherto immunosuppressed spleen cells from BALB/c mice bearing a large MOPC-315 tumor (in contrast to spleen cells from normal mice) acquire the ability to generate a greatly enhanced anti-MOPC-315 cytotoxic T lymphocyte (CTL) response upon in vitro stimulation with MOPC-315 tumor cells. Here we show that the catecholamines norepinephrine, epinephrine, and isoproterenol suppressed the in vitro generation of anti-MOPC-315 cytotoxicity by spleen cells from mice that had just completed the eradication of a large MOPC-315 tumor following low-dosel-PAM therapy (l-PAM TuB spleen cells), as well as by spleen cells from normal mice. In contrast to the marked suppression obtained with catecholamines, the cholinergic agonist carbachol had no effect on the in vitro generation of splenic anti-MOPC-315 cytotoxicity. The inhibitory effect of the catecholamines was “mimicked” by the membranepenetrating analog of cAMP, dibutyryl-cAMP, and by cholera toxin at concentrations that stimulate the endogenous production of cAMP. The β-adrenergic receptor antagonist propranolol did not block norepinephrine-induced inhibition of the generation of anti-MOPC-315 cytotoxicity by either normal orl-PAM TuB spleen cells. Since the curative effectiveness of low-dosel-PAM therapy for MOPC-315 tumor bearers requires the participation of CD8+ T cells that exploit a CTL response in tumor eradication, it is conceivable that norepinephrine may reduce the therapeutic outcome of low-dose chemotherapy by inhibiting the acquisition of CTL activity.

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References

  1. Ben-Efraim S, Bocian RC, Mokyr MB, Dray S (1983) Increase in the effectiveness of melphalan therapy with progression of MOPC-315 plasmacytoma tumor growth. Cancer Immunol Immunother 15:101.

    PubMed  Google Scholar 

  2. Besedovsky HO, DelRey A, Sorkin E, DaPrada M, Keller HH (1979) Immunoregulation mediated by the sympathetic nervous system. Cell Immunol 48:346

    PubMed  Google Scholar 

  3. Burton RC, Thompston J, Warner NL (1975) In vitro induction of tumor specific immunity. J Immunol Methods 8:133

    PubMed  Google Scholar 

  4. Carlson SL, Brooks WH, Roszman TL (1989) Neurotransmitter-lymphocyte interactions: dual receptor modulation of lymphocyte proliferation and cAMP production. J Neuroimmunol 24:155

    PubMed  Google Scholar 

  5. Chambers DA, Cohen RL, Perlman RL (1993) Neuroimmune modulation: signal transduction and catecholamines. Neurochem Int 22:95

    PubMed  Google Scholar 

  6. Chambers DA, Martin DW Jr, Weinstein Y (1974) The effect of cyclic nucleotides on purine biosynthesis and the induction of PRPP synthetase during lymphocyte activation. Cell 3:375

    PubMed  Google Scholar 

  7. Coffey RG, Hadden JW (1985) Neurotransmitters, hormones, cyclic nucleotides in lymphocyte regulation. Fed Proc 44:112

    PubMed  Google Scholar 

  8. Cook-Mills J, Jacobson P, Perlman R, Chambers DA (1988) Norepinephrine modulation of T and B-cell proliferation. FASEB J 2:A311

    Google Scholar 

  9. Daniel V, Bourne HR, Tomkins GM (1973) Altered metabolism and endogenous cyclic AMP in cultured cells deficient in cyclic AMP-binding protein. Nature 244:167

    PubMed  Google Scholar 

  10. Ellenhorn JDI, Schreiber H, Bluestone JA (1990) Mechanism of tumor rejection in anti-CD3 monoclonal antibody-treated mice. J Immunol 144:2840

    PubMed  Google Scholar 

  11. Felten DL, Felten SY, Carlson SL, Olschowka JA, Livnat S (1985) Noradrenergic and peptidergic innervation of lymphoid tissue. J Immunol 135:755s

    Google Scholar 

  12. Felten DL, Felten SY, Bellinger DL, Carlson SL, Ackerman KD, Madden KS, Olschowka JA, Livnat S (1987) Noradrenergic sympathetic neural interactions with the immune system: structure and function. Immunol Rev 100:225

    PubMed  Google Scholar 

  13. Fuchs BA, Campbell KS, Munson AE (1988) Norepinephrine and serotonin content of the murine spleen: its relationship to lymphocyte β-adrenergic receptor density and the humoral immune response in vivo and in vitro. Cell Immunol 117:339

    PubMed  Google Scholar 

  14. Hadden JW, Hadden EM, Middleton E Jr (1970) Lymphocyte blast transformation. 1. Demonstration of adrenergic receptors in human peripheral lymphocytes. Cell Immunol 1:583

    PubMed  Google Scholar 

  15. Hatfield SM, Petersen BH, Dimicco JA (1986) Beta adrenoceptor modulation of the generation of murine cytotoxic T lymphocytes in vitro. J Pharmacol Exp Ther 239:460

    PubMed  Google Scholar 

  16. Hill JO, Awwad M, North RJ (1989) Elimination of CD4+ suppressor T cells from susceptible BALB/c mice releases CD8+ T lymphocytes to mediate protective immunity against Leishmania. J Exp Med 169:1819

    PubMed  Google Scholar 

  17. Hughes RJ, Mahan LC, Insel PA (1988) Certain β-blockers can decrease β-adrenergic receptor number. II. Down regulation of receptor number by alprenolol and propranolol in cultured lymphoma and muscle cells. Circ Res 63:279

    PubMed  Google Scholar 

  18. Khan MM, Sansoni P, Silverman ED, Engleman EG, Melmon KL (1986) Beta-adrenergic receptors on human suppressor, helper, and cytolytic lymphocytes. Biochem Pharmacol 35:1137

    PubMed  Google Scholar 

  19. Loveland BE, Jarrott B, McKenzie IFC (1981) The detection of β-adrenoceptors on murine lymphocytes. Int J Immunopharmacol 3:45

    PubMed  Google Scholar 

  20. Madden KS, Livnat S (1991) Catecholamine action and immunologic reactivity: In: Ader R, Felten DL, Cohen N (eds) Psychoneuroimmunology, 2nd edn. Academic Press, San Diego, p 283

    Google Scholar 

  21. Mokyr MB, Braun DP, Usher D, Reiter H, Dray S (1978) The development of in vitro and in vivo antitumor cytotoxicity in noncytotoxic tumor bearer spleen cells “educated” in vitro with MOPC-315 tumor cells. Cancer Immunol Immunother 4:143

    Google Scholar 

  22. Mokyr MB, Barker E, Weiskirch LM, Takesue BY, Pyle JM (1989) Importance of Lyt 2+ T-cells in the curative effectivenes of a low dose of melphalan for mice bearing a large MOPC-315 tumor. Cancer Res 49:4597

    PubMed  Google Scholar 

  23. Niaudet P, Beauraine G, Bach MA (1976) Differences in effect of isoproterenol stimulation on levels of cyclic AMP in human B and T lymphocytes. Eur J Immunol 6:834

    PubMed  Google Scholar 

  24. O'Dorisio MS, Wood CL, O'Dorisio TM (1985) Vasoactive intestinal peptide and neuropeptide modulation of the immune response. J Immunol 135:7925

    Google Scholar 

  25. Rasenick MM, Kaplan RS (1986) Guanine nucleotide activation of adenylate cyclase in saponin permeabilized glioma cells. FEBS Lett 207:296

    PubMed  Google Scholar 

  26. Rollinghoff M, Rouse BT, Warner NL (1973) Tumor immunity to murine plasma cell tumors. I. Tumor-associated transplantation antigens of NZB and BALB/c plasma cell tumors. J Natl Cancer Inst 50:159

    PubMed  Google Scholar 

  27. Roszman TL, Brooks WH (1990) Signaling pathways of the neurotransmitter-immune network: In: Freier S (ed) The neuroendocrine-immune network. CRC, Boca Raton, Fla, p 53

    Google Scholar 

  28. Saloman Y (1979) Adenylate cyclase assay. Adv Cyclic Nucleotide Res 10:35

    PubMed  Google Scholar 

  29. Simpson JR, Hoffman-Goetz L (1990) Exercise stress and murine natural killer cell function. Proc Soc Exp Biol Med 195:129

    PubMed  Google Scholar 

  30. Steel RGD, Torrie JH (1980) Principles and procedures of statistics. McGraw Hill, 1980, pp 188–189

  31. Strom TD, Lundin AP, Carpenter CB (1977) The role of cyclic nucleotides in lymphocyte activation and function. Prog Clin Immunol 3:115

    PubMed  Google Scholar 

  32. Sugiyama H, Chen P, Hunter M, Taffs R, Sitkovsky M (1992) The dual role of the cAMP-dependent protein kinase Cα subunit in T-cell receptor-triggered T-lymphocytes effector functions. J Biol Chem 267:25256

    PubMed  Google Scholar 

  33. Takesue BY, Pyle JM, Mokyr MB (1990) Importance of tumor-specific cytotoxic CD8+ T-cells in eradication of a large subcutaneous MOPC-315 tumor following low-dose melphalan therapy. Cancer Res 50:7641

    PubMed  Google Scholar 

  34. Vischer TL (1976) The differential effect of cyclic AMP on lymphocyte stimulation by T- or B-cell mitogens. Immunology 30:735

    PubMed  Google Scholar 

  35. Watson J (1975) The influence of intracellular levels of cyclic nucleotides on cell proliferation and the induction of antibody synthesis. J Exp Med 141:97

    PubMed  Google Scholar 

  36. Widmer MB, Grabstein KH (1987) Regulation of cytolytic T-lymphocyte generation by B-cell stimulatory factor. Nature 326:795

    PubMed  Google Scholar 

  37. Williams LT, Synderman R, Lefkowitz RJ (1976) Identification of β-adrenergic receptors in human lymphocytes by (−)[3H]-alprenolol binding. J Clin Invest 57:149

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Center for Molecular Biology of Oral Diseases, University of Illinois at Chicago, USA

    Joan M. Cook-Mills, Rhonna L. Cohen & Donald A. Chambers

  2. Department of Biochemistry, University of Illinois College of Medicine, 1853 West Polk Street (M/C 536), 60612, Chicago, IL, USA

    Margalit B. Mokyr & Donald A. Chambers

  3. Departments of Pediatrics and of Pharmacological and Physiological Sciences, The University of Chicago, USA

    Robert L. Perlman

  4. The Joseph P. Kennedy Jr. Mental Retardation Research Center, The University of Chicago, USA

    Robert L. Perlman

Authors
  1. Joan M. Cook-Mills
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  2. Margalit B. Mokyr
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  3. Rhonna L. Cohen
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  4. Robert L. Perlman
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  5. Donald A. Chambers
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Cook-Mills, J.M., Mokyr, M.B., Cohen, R.L. et al. Neurotransmitter suppression of the in vitro generation of a cytotoxic T lymphocyte response against the syngeneic MOPC-315 plasmacytoma. Cancer Immunol Immunother 40, 79–87 (1995). https://doi.org/10.1007/BF01520288

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  • DOI: https://doi.org/10.1007/BF01520288

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