Rameshwar P, Gascon P, Ganea D
Department of Biological Sciences, Rutgers University, Newark, NJ 07102.
J Immunol. 1993 Sep 1;151(5):2484-96.
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.
P物质（SP）是一种速激肽神经肽，先前有报道称其可刺激经佛波酯激活的小鼠T细胞系产生白细胞介素-2（IL-2）。在此，我们通过确定SP及相关速激肽对正常小鼠淋巴细胞和纯化的CD4⁺ T细胞产生IL-2的刺激作用，扩展了这些观察结果。结果表明，SP是最有效的IL-2诱导剂，其发挥最大作用的浓度比 Physalaemin、神经激肽A（NKA）或神经激肽B（NKB）的最佳刺激浓度低4至5个数量级。SP以剂量依赖性方式刺激IL-2的产生，最佳浓度范围为10⁻¹⁰至10⁻¹⁴ M，这与在血液和其他器官中发现的SP生理浓度相当。SP的作用由分子的羧基末端部分（SP4 - 11）介导。速激肽拮抗剂spantide和NK-1型受体特异性非肽拮抗剂CP-96,345的抑制作用证实了SP活性的特异性。在未分级的脾细胞培养物中，SP诱导了IL-2蛋白的从头合成。SP可以直接诱导IL-2的产生，也可以与刀豆蛋白A（Con A）或抗CD3抗体处理联合诱导。SP与Con A联合使用时具有协同作用，而与抗CD3抗体联合使用时具有相加作用，这表明这些刺激因子的分子机制不同。在没有额外共刺激的情况下，未分级脾细胞培养物中SP的作用部分通过诱导IL-1介导，并且在纯化的CD4⁺ T细胞中，IL-2的诱导需要SP和IL-1两者。与对IL-2产生的刺激作用相反，SP并未诱导小鼠脾细胞产生γ干扰素（IFN-γ）。SP对IL-2产生的刺激作用表明，SP一些已描述的免疫刺激活性可能是通过正常淋巴细胞中IL-2产生的上调介导的。
