Blum A M, Elliott D E, Metwali A, Li J, Qadir K, Weinstock J V
Department of Internal Medicine, University of Iowa, Iowa City 52242, USA.
J Immunol. 1998 Dec 1;161(11):6316-22.
Substance P (SP) and somatostatin (SOM) are made at mucosal surfaces and sites of inflammation. There is a SP/SOM immunoregulatory circuit that modulates the IFN-gamma response in murine schistosomiasis. SP enhances, while SOM decreases, IFN-gamma secretion. Various inflammatory mediators induce macrophages to make SOM, but no known factor limits this expression. It was discovered that SP regulates SOM synthesis. Splenocytes from normal, uninfected mice cultured with LPS, IFN-gamma, or IL-10 for 4 h strongly expressed SOM mRNA, but failed to do so in the presence of SP. The inhibition with 10(-9) M SP was > 85% shown by quantitative PCR. Also, splenocyte SOM content decreased from 1048 +/- 275 to < 10 pg/4 x 10(8) cells following SP exposure. Immunohistochemistry identified SOM solely within splenic macrophages following cytokine stimulation. Mice infected with Schistosoma mansoni form granulomas in the liver and intestines resulting from deposition of parasite eggs in these organs. The granulomas contain macrophages that make SOM constitutively. SP at 10(-8) M decreased SOM mRNA expression > 90% in dispersed granuloma cells cultured for 4 h or longer. Specific SP receptor antagonists blocked SP suppression of SOM expression in splenocytes and dispersed granuloma cells, showing that an authentic SP receptor mediated the regulation. Additional studies revealed that IL-4 antagonized the SP effect in the spleen. It is concluded that in granulomas and splenocytes from mice with schistosomiasis and in splenocytes from uninfected animals that 1) SP inhibits macrophage SOM induction and ongoing expression at the mRNA and protein levels acting through the SP receptor, and 2) IL-4 can antagonizes this SP effect.
P物质（SP）和生长抑素（SOM）在黏膜表面和炎症部位产生。存在一个SP/SOM免疫调节回路，可调节小鼠血吸虫病中的γ干扰素反应。SP增强γ干扰素分泌，而SOM则减少γ干扰素分泌。多种炎症介质诱导巨噬细胞产生SOM，但尚无已知因子限制这种表达。研究发现SP可调节SOM的合成。来自正常未感染小鼠的脾细胞与脂多糖、γ干扰素或白细胞介素-10培养4小时后强烈表达SOM mRNA，但在有SP存在时则未能表达。定量PCR显示，10⁻⁹ M的SP抑制率>85%。此外，暴露于SP后，脾细胞SOM含量从1048±275降至<10 pg/4×10⁸个细胞。免疫组织化学鉴定发现，细胞因子刺激后，SOM仅存在于脾巨噬细胞中。感染曼氏血吸虫的小鼠在肝脏和肠道形成肉芽肿，这是由于寄生虫卵在这些器官中沉积所致。肉芽肿中含有组成性产生SOM的巨噬细胞。10⁻⁸ M的SP可使培养4小时或更长时间的分散肉芽肿细胞中SOM mRNA表达降低>90%。特异性SP受体拮抗剂可阻断SP对脾细胞和分散肉芽肿细胞中SOM表达的抑制作用，表明真正的SP受体介导了这种调节。进一步研究发现，白细胞介素-4可拮抗SP在脾脏中的作用。得出的结论是，在血吸虫病小鼠的肉芽肿和脾细胞以及未感染动物的脾细胞中，1）SP通过SP受体在mRNA和蛋白质水平抑制巨噬细胞SOM的诱导和持续表达，2）白细胞介素-4可拮抗这种SP作用。
