Inhibition of type II collagen-induced arthritis in rats by triptolide

Abstract

The effects of purified triptolide, a diterpenoid triepoxide compound derived from the Chinese traditional anti-rheumatic medicinal plant extract, Tripterygium wilfordii Hook f (TWHf), were determined in type II collagen-induced arthritis (CIA) in rats. Lewis rats were immunized with bovine type II collagen and treated with purified triptolide 0.1 mg\kg\day or control (vehicle for triptolide) by daily gavage feedings for 28 days. Triptolide was well-tolerated with no evidence of toxicity. Treatment with triptolide resulted in significant delay in time to onset of arthritis (P = 0.039), as well as significantly decreased arthritis incidence (P = 0.024), clinical arthritis severity score (P < 0.0001), histopathological arthritis severity score (P < 0.0001), and in vivo cell-mediated immunity to collagen (P = 0.0004). Triptolide appeared to be a potent immunomodulatory inhibitor of CIA in rats and this may account for the previously observed anti-rheumatic properties of crude extracts of TWHf, although more extensive studies will be needed to confirm these effects.

Introduction

Extracts of the root of Tripterygium wilfordii Hook f (TWHf), a vine-like member of the Celastraceae plant family, have been used in Chinese traditional medicine for the treatment of autoimmune diseases and inflammatory dermatoses including rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, Henoch-Schonlein purpura, Behçet’s disease, psoriasis, and erythema nodosum (Wenyan et al., 1985). We previously demonstrated that orally administered crude TWHf extract inhibited type II collagen-induced arthritis (CIA) in DBA\1LacJ mice (Gu et al., 1992b), and attenuated immune complex-mediated glomerulonephritis resulting in decreased mortality in MRL-lpr\lpr ’lupus’ mice (Gu et al., 1992a). Crude TWHf extracts have been demonstrated to inhibit IL 2 production and T cell proliferation in vitro , suggesting an immunosuppressive mode of action (Tao et al., 1991).

Anumber of compounds have been isolated from whole TWHf root or cultured plant cell lines and chemically characterized including diterpenes (triptolide, tripdiolide, triptonide, dehydroabietic acid), quinone methide triterpenes (celastrol), other triterpenes (oleanolic acid, pulpononic acid), alkaloids, glycosides, dulcitols, wilfordine, β-sitosterol, and triptoquinones (Kupchan et al., 1972; Kutney et al. 1981, Kutney et al. 1992; Takaishi et al., 1992). Other novel compounds isolated from TWHf include the diterpene lactone, tripterifordin (Chen et al., 1992a), and salaspermic acid (Chen et al., 1992b). The biologic activities of the latter two compounds include cytotoxicity to HIV-infected T cells.

The diterpenoid triepoxide, triptolide (Fig. 1), was originally isolated from TWHf based on its biologic activities including cytotoxicity against human nasopharyngeal carcinoma cells in vitro and against murine leukemia in vivo (Kupchan et al., 1972). Triptolide is a potent inhibitor of IL 2 production by T cells in vitro (Tao et al., 1992) and prolongs skin allograft survival in mice (Yang et al., 1992). The purpose of the present pilot study was to determine whether purified triptolide inhibits type II CIA in rats. This observation would support its putative role as a biologically active component of TWHf.