The Journal of Immunology, Vol 151, Issue 5 2484-2496, Copyright © 1993 by American Association of Immunologists

ARTICLES

Stimulation of IL-2 production in murine lymphocytes by substance P and related tachykinins

P Rameshwar, P Gascon and D Ganea
Department of Biological Sciences, Rutgers University, Newark, NJ 07102.

Substance P (SP), a tachykinin neuropeptide, has been previously reported to stimulate IL-2 production in murine T cell lines activated with phorbol esters. Here we extend these observations by establishing the stimulatory effect of SP and related tachykinins on IL-2 production by normal murine lymphocytes and on purified CD4+ T cells. SP proved to be the most efficient IL-2 inducer, exerting its maximal effect at concentrations that were 4 to 5 orders of magnitude lower than the optimal stimulatory concentrations of physalaemin, NKA, or NKB. SP stimulated IL-2 production in a dose-dependent manner, with an optimal concentration range of 10(-10) to 10(-14) M, comparable with physiologic concentrations of SP found in blood and other organs. The effect of SP was carried by the carboxyl-terminal part of the molecule (SP4-11). The specificity of SP activity was confirmed by the inhibitory effect of spantide, a tachykinin antagonist, and of CP- 96,345, a nonpeptide antagonist specific for NK-1-type receptors. In unfractionated spleen cell cultures SP induced de novo IL-2 protein synthesis. SP could induce IL-2 production either directly, or in combination with Con A or anti-CD3 antibody treatments. The effect of SP in conjunction with Con A was synergistic, whereas the effect in conjunction with anti-CD3 antibodies was additive, suggesting different molecular mechanisms for these stimulatory factors. In the absence of additional costimuli the effect of SP in unfractionated spleen cell cultures was partially mediated through the induction of IL-1, and both SP and IL-1 were required for IL-2 induction in purified CD4+ T cells. In contrast to its stimulatory effect on the generation of IL-2, SP did not induce IFN-gamma production in murine spleen cells. The stimulatory effect of SP on IL-2 production suggests that some of the already described immunostimulatory activities of SP could be mediated through the up-regulation of IL-2 production in normal lymphocytes.

This article has been cited by other articles:

				G. Li, G. Cui, N.-S. Tzeng, S.-J. Wei, T. Wang, M. L. Block, and J.-S. Hong Femtomolar concentrations of dextromethorphan protect mesencephalic dopaminergic neurons from inflammatory damage FASEB J, April 1, 2005; 19(6): 489 - 496. [Abstract] [Full Text] [PDF]

				R. A. Joachim, V. Sagach, D. Quarcoo, Q. T. Dinh, P. C. Arck, and B. F. Klapp Neurokinin-1 Receptor Mediates Stress-Exacerbated Allergic Airway Inflammation and Airway Hyperresponsiveness in Mice Psychosom Med, July 1, 2004; 66(4): 564 - 571. [Abstract] [Full Text] [PDF]

				F.T. Lundy and G.J. Linden NEUROPEPTIDES AND NEUROGENIC MECHANISMS IN ORAL AND PERIODONTAL INFLAMMATION Crit. Rev. Oral. Biol. Med., March 1, 2004; 15(2): 82 - 98. [Abstract] [Full Text]

				D. D. Joshi, A. Dang, P. Yadav, J. Qian, P. S. Bandari, K. Chen, R. Donnelly, T. Castro, P. Gascon, A. Haider, et al. Negative feedback on the effects of stem cell factor on hematopoiesis is partly mediated through neutral endopeptidase activity on substance P: a combined functional and proteomic study Blood, November 1, 2001; 98(9): 2697 - 2706. [Abstract] [Full Text] [PDF]

				B. Liu, L. Qin, S.-N. Yang, B. C. Wilson, Y. Liu, and J.-S. Hong Femtomolar Concentrations of Dynorphins Protect Rat Mesencephalic Dopaminergic Neurons against Inflammatory Damage J. Pharmacol. Exp. Ther., September 1, 2001; 298(3): 1133 - 1141. [Abstract] [Full Text] [PDF]

				M. T. Tran, R. N. Lausch, and J. E. Oakes Substance P Differentially Stimulates IL-8 Synthesis in Human Corneal Epithelial Cells Invest. Ophthalmol. Vis. Sci., November 1, 2000; 41(12): 3871 - 3877. [Abstract] [Full Text]

				L. E. MILLER, H.-P. JÜSTEN, J. SCHÖLMERICH, and R. H. STRAUB The loss of sympathetic nerve fibers in the synovial tissue of patients with rheumatoid arthritis is accompanied by increased norepinephrine release from synovial macrophages FASEB J, October 1, 2000; 14(13): 2097 - 2107. [Abstract] [Full Text]

				R. Dimri, Y. Sharabi, and J. Shoham Specific Inhibition of Glucocorticoid-Induced Thymocyte Apoptosis by Substance P J. Immunol., March 1, 2000; 164(5): 2479 - 2486. [Abstract] [Full Text] [PDF]

				D. Eskinazi Homeopathy Re-revisited: Is Homeopathy Compatible With Biomedical Observations? Arch Intern Med, September 27, 1999; 159(17): 1981 - 1987. [Full Text] [PDF]

				A. M. Blum, D. E. Elliott, A. Metwali, J. Li, K. Qadir, and J. V. Weinstock Substance P Regulates Somatostatin Expression in Inflammation J. Immunol., December 1, 1998; 161(11): 6316 - 6322. [Abstract] [Full Text] [PDF]