EFFECT OF SUBSTANCE-P ON CYTOKINE PRODUCTION BY HUMAN ASTROCYTIC CELLS AND BLOOD MONONUCLEAR-CELLS - CHARACTERIZATION OF NOVEL TACHYKININ RECEPTOR ANTAGONISTS

Substance P (SP) has been reported to induce inflammatory cytokine pro duction in human neuroglial cells and peripheral lymphoid cells as wel l, In order to evaluate the potency of novel non-peptide antagonists o f the tachykinin receptors as inhibitors of SP-induced cytokines, we u sed the astrocytoma cell line U373MG and blood mononuclear cells as mo dels of central and peripheral SP-target cells, respectively, In the f irst part of this study, we showed that SR 140333, an NK1 tachykinin r eceptor antagonist, was able to inhibit strongly the SP-induced produc tion of interleukin (IL)-6 and IL-8 in the astrocytoma cell line, The antagonistic activity of SR 140333 toward SP-induced cytokine producti on was specific and could not be attributed to a general anti-cytokine effect, since cytokine release induced by another inflammatory protei n such as IL-1 beta 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 magnit ude lower inhibitory potency than SR 140333, All these data indicated that SR 140333 blocked SP-induced cytokine production in U373MG astroc ytic cells via a specific NK1 receptor-mediated process, Since SP has also been described to trigger peripheral blood mononuclear cells (PBM NC) or monocytes to release inflammatory cytokines, we attempted, in t he second part of this study, to evaluate the potential antagonistic e ffect 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 tha t SP at concentrations ranging from 0.1 to 1000 nM was unable to stimu late 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.