title: Different susceptibility to neurokinin 1 receptor antagonists of substance P and septide-induced interleukin-6 release from U373 MG human astrocytoma cell line.
abstract: In a human astrocytoma cell line U373 MG, the activation of the neurokinin 1 (NK1) receptor by substance P (SP) increase, in a concentration-related manner (1 nM to 10 microM), the basal release of interleukin-6 (IL-6) as assayed by an ELISA method, in cell supernatants after 18 h of incubation. Septide, a selective NK1 receptor agonist, is equipotent to SP in inducing the IL-6 release showing similar Emax (2644 +/- 285 and 2830 +/- 271 pg/ml) and EC50 (15.6 +/- 3.6 and 13.8 +/- 3.2 nM). However, in binding assays on intact cells, septide was an about 50-fold weaker displacer of the binding of [3H][Sar9,Met(O2)11]SP than SP (Ki's were 0.28 +/- 0.1 nM and 14.2 +/- 5.0 nM for SP and septide, respectively). NK2- and NK3-selective agonists (up to 1 microM) had no binding or functional effect. Highly selective non-peptide (CP96,345) or peptide (GR82,334) NK1 receptor antagonists were more effective in antagonizing septide-(IC50's 0.2 +/- 0.06 nM and 70 +/- 18 nM) than SP-(IC50's 6.7 +/- 1.3 nM and 1.95 +/- 0.4 microM) induced IL-6 secretion. These data support the existence, also in human U373 MG cells, of a septide-sensitive NK1 receptor subtype(s) and/or epitope(s) blocked with high affinity by NK1 antagonist.
authors.affiliation: Menarini Ricerche Sud, Pharmacology Department, Pomezia, Roma, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Palma
authors.forename: C
authors.initials: C
authors.lastname: Goso
authors.forename: S
authors.initials: S
authors.lastname: Manzini
mesh_terms: D001254:Astrocytoma / Q000378:metabolism*; D001667:Binding, Competitive / Q000187:drug effects; D001932:Brain Neoplasms / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D064729:Neurokinin-1 Receptor Antagonists; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives; D013373:Substance P / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D015850:Interleukin-6; D064729:Neurokinin-1 Receptor Antagonists; D010446:Peptide Fragments; D013373:Substance P; C054725:septide; D011761:Pyrrolidonecarboxylic Acid