Derocq J M, Ségui M, Blazy C, Emonds-Alt X, Le Fur G, Brelire J C, Casellas P
Sanofi Recherche, Montpellier, France.
FEBS Lett. 1996 Dec 16;399(3):321-5. doi: 10.1016/s0014-5793(96)01346-4.
Substance P (SP) has been reported to induce inflammatory cytokine production in human neuroglial cells and peripheral lymphoid cells as well. In order to evaluate the potency of novel non-peptide antagonists of the tachykinin receptors as inhibitors of SP-induced cytokines, we used the astrocytoma cell line U373MG and blood mononuclear cells as models of central and peripheral SP-target cells, respectively. In the first part of this study, we showed that SR 140333, an NK1 tachykinin receptor antagonist, was able to inhibit strongly the SP-induced production of interleukin (IL)-6 and IL-8 in the astrocytoma cell line. The antagonistic activity of SR 140333 toward SP-induced cytokine production was specific and could not be attributed to a general anti-cytokine effect, since cytokine release induced by another inflammatory protein such as IL-1beta was not blocked by this compound. In addition, NK2 and NK3 agonist neuropeptides were at least 1000-fold less effective than SP, while SR 48968 and SR 142801 which are selective NK2 and NK3 receptor antagonists, respectively, displayed a 2.5-3 orders of magnitude lower inhibitory potency than SR 140333. All these data indicated that SR 140333 blocked SP-induced cytokine production in U373MG astrocytic cells via a specific NK1 receptor-mediated process. Since SP has also been described to trigger peripheral blood mononuclear cells (PBMNC) or monocytes to release inflammatory cytokines, we attempted, in the second part of this study, to evaluate the potential antagonistic effect of our compounds on these cells. Experiments on human PBMNC from different donors were carried out to determine first their pattern of cytokine production upon SP stimulation. Surprisingly, we noticed that SP at concentrations ranging from 0.1 to 1000 nM was unable to stimulate the release of any inflammatory cytokine tested. This raises the question of the specificity of the reported in vitro effects of SP on cytokine production by human peripheral immune cells.
据报道，P物质（SP）可诱导人神经胶质细胞以及外周淋巴细胞产生炎性细胞因子。为了评估新型速激肽受体非肽拮抗剂作为SP诱导细胞因子抑制剂的效力，我们分别使用星形细胞瘤细胞系U373MG和血液单核细胞作为中枢和外周SP靶细胞的模型。在本研究的第一部分，我们表明NK1速激肽受体拮抗剂SR 140333能够强烈抑制星形细胞瘤细胞系中SP诱导的白细胞介素（IL）-6和IL-8的产生。SR 140333对SP诱导的细胞因子产生的拮抗活性具有特异性，不能归因于一般的抗细胞因子作用，因为该化合物不会阻断由另一种炎性蛋白如IL-1β诱导的细胞因子释放。此外，NK2和NK3激动剂神经肽的效力比SP至少低1000倍，而分别作为选择性NK2和NK3受体拮抗剂的SR 48968和SR 142801的抑制效力比SR 140333低2.5至3个数量级。所有这些数据表明，SR 140333通过特定的NK1受体介导的过程阻断了U373MG星形胶质细胞中SP诱导的细胞因子产生。由于SP也被描述为可触发外周血单核细胞（PBMNC）或单核细胞释放炎性细胞因子，因此在本研究的第二部分，我们试图评估我们的化合物对这些细胞的潜在拮抗作用。我们对来自不同供体的人PBMNC进行了实验，首先确定它们在SP刺激下的细胞因子产生模式。令人惊讶的是，我们注意到浓度范围为0.1至1000 nM的SP无法刺激所测试的任何炎性细胞因子的释放。这就引发了关于所报道的SP对人外周免疫细胞产生细胞因子的体外作用特异性的问题。
