Effects of KE-758; an active metabolite of the new anti-rheumatic drug KE-298, D-penicillamine, bucillamine and auranofin on the proliferation of murine lymphocytes, and the production of nitric oxide by murine macrophages

Citation
T. Inoue et al., Effects of KE-758; an active metabolite of the new anti-rheumatic drug KE-298, D-penicillamine, bucillamine and auranofin on the proliferation of murine lymphocytes, and the production of nitric oxide by murine macrophages, INT IMMUNO, 1(5), 2001, pp. 833-842
Citations number
23
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Immunology
Journal title
INTERNATIONAL IMMUNOPHARMACOLOGY
ISSN journal
1567-5769 → ACNP
Volume
1
Issue
5
Year of publication
2001
Pages
833 - 842
Database
ISI
SICI code
1567-5769(200105)1:5<833:EOKAAM>2.0.ZU;2-L
Abstract
2-Mercaptomethyl-4-(4-methylphenyl)-4-oxobutanoic acid (KE-758), which is t he active metabolite of 2-acrtylthiomethyl-4-(4-merhylphenyl)-4-oxobutanoic acid (KE-298), is a novel sulphydryl anti-rheumatic drug. In this study we analyzed the effect of KE-758 on the proliferation of murine lymphocytes, and on the production of nitric oxide (NO) by RAW264.7 murine macrophage ce lls. We compared its effect with other sulphydryl drugs such as D-penicilla mine, bucillamine and auranofin. The proliferation of lymphocytes was measu red by H-3-thymidine incorporation assay. Nitrite was measured using Griess Reagent. In the absence of copper ions, KE-758, D-penicillamine and bucill amine rarely affected the proliferation of concanavarin A (ConA) activated murine splenocytes. However, in the presence of copper, pharmacological con centrations of KE-758 but not D-penicillamine and bucillamine suppressed th e proliferation of murine splenocytes through a hydrogen peroxide-dependent mechanism. Auranofin markedly suppressed the proliferation regardless of t he presence of copper ions by reducing the cellular viability. Furthermore, only KE-758 markedly suppressed the proliferation of phorbol myristate ace tate (PMA) plus ionomycin activated murine whole blood lymphocytes (WBL) ev en in the absence of exogenous copper ions by a hydrogen peroxide-independe nt mechanism. Meanwhile, lipopolysaccharide (LPS) or LPS plus interferon-ga mma (IFN-gamma) induced NO production by RAW264.7 cells were suppressed by KE-758 and auranofln but not by D-penicillamine and bucillamine. In conclus ion, KE-758 is a novel immunosuppressive drug, which inhibits both lymphocy te and macrophage functions and its unique anti-rheumatic profile is distin ct from that of D-penicillamine. bucillamine and auranofin. (C) 2001 Elsevi er Science B.V. All rights reserved.