FUNCTIONAL-CHARACTERIZATION OF SUBSTANCE-P RECEPTORS ON CULTURED HUMAN SPINAL-CORD ASTROCYTES - SYNERGISM OF SUBSTANCE-P WITH CYTOKINES IN INDUCING INTERLEUKIN-6 AND PROSTAGLANDIN E-2 PRODUCTION

Following brain injury, astrocytes express receptors for cytokines and neuropeptides and secrete several regulatory mediators that have a we ll established role in inflammation, immunity, and tissue development or repair. To elucidate the role of substance P (SP), a neurotransmitt er peptide of the tachykinin family, in inducing astrocyte secretory a ctivities, we have examined the expression of SP receptors and the fun ctional consequences of their activation in cultured astrocytes from t he human embryonic brain or spinal cord. Radioligand binding studies r evealed that only one type of SP receptors, the high affinity NK-1 rec eptor, was present on human astrocytes and that spinal cord astrocytes expressed about 6 times as many SP binding sites as brain astrocytes. Following SP treatment, a substantial inositol phosphate formation wa s observed in spinal cord astrocytes only. Stimulation of spinal cord astrocytes with SP alone did not induce secretion of cytokines [interl eukin-6 (IL-6), granulocyte-macrophage-CSF, macrophage chemoattractant protein-1 or leukemia inhibitory factor] or prostaglandin E-2 (PGE(2) ). Interestingly, however, SP selectively potentiated the inducing eff ect of IL-1 beta on IL-6 and PGE(2) secretion by spinal cord astrocyte s without affecting the IL-1-beta-evoked secretion of other cytokines. SP also enhanced the small inducing effect of tumor necrosis factor-a lpha (TNF-alpha) on IL-6 and PGE(2) secretion and that of transforming growth factor-beta on PGE(2) secretion. These results suggest that SP can enhance immunoregulatory and neurotrophic astroglial functions me diated by IL-6 and PGE(2) by acting in concert with a set of cytokines whose cerebral expression has been reported during development and in a variety of diseases. (C) 1997 Wiley-Liss, Inc.