International Journal of Immunopharmacology
Inhibition of type II collagen-induced arthritis in rats by triptolide
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.
Section snippets
Animals
Inbred female Lewis rats, age 8 weeks, weight 130–150 g (Charles River, Wilmington, MA), were fed standard laboratory chow and water ad libitum.
Reagents
Bovine type II collagen (BII) was obtained from Sigma Chemical Co. (St Louis, MO) and incomplete Freund’s adjuvant (ICFA) from Difco Laboratories (Detroit, MI). Purified triptolide was provided by Professor James Kutney, University of British Columbia (Vancouver, BC, Canada). This had been isolated from TWHf plant cell cultures (Kutney et al., 1981).
Clinical assessment
All animals tolerated the experimental procedures well with no evidence of drug toxicity and no deaths up to the study termination at Day 28. The onset and distribution of arthritis were similar to the pattern previously described (Cremer, 1988). Arthritis was additive in nature and predominantly hindpaw in distribution at onset with forepaw involvement occurring only late in the course of the experiment. The clinical indices of arthritis over the 28 day period post-immunization are summarized
Discussion
The results of this study indicate that purified triptolide is a potent immunomodulatory inhibitor of type II CIA in rats. More extensive studies will be needed to confirm these results. We have not evaluated the effects of other compounds purified from TWHf in animal models of rheumatic diseases. However, we recently fractionated the chemical components of crude TWHf by HPLC, using an MLR assay to screen for immunomodulatory activity, with the compounds isolated structurally characterized by
Acknowledgements
The authors are grateful to Professor James Kutney, Department of Chemistry, University of British Columbia, for providing purified triptolide, and Dr Subhashis Banerjee, BASF Corporation, for helpful advice regarding the anti-collagen antibody assay.
References (28)
- et al.
Immunol.
(1984) - et al.
J.
(1991) - et al.
Int. J. Immunopharmac.
(1995) - et al.
Tetrahedron Lett.
(1992) - et al.
J. Exp. Med.
(1988) - et al.
J. Immunol.
(1988) - et al.
Lab. Invest.
(1982) - et al.
AIDS
(1992) - et al.
AIDS
(1992) - Cremer, M., 1988. Type II collagen-induced arthritis in rats. In: Greenwald, R.A., Diamond, H.S. (Eds.), Handbook of...
Science
Arthritis Rheum.
J.Rheumatol.
Cited by (104)
Triptolide induces p53-dependent cardiotoxicity through mitochondrial membrane permeabilization in cardiomyocytes
2018, Toxicology and Applied PharmacologyCitation Excerpt :The extracts of TWHF have been approved as a therapeutic agent for rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and ankylosing spondylitis (AS) by the China Food and Drug Administration (CFDA) (Ji et al., 2010). Triptolide (TP), a highly promising diterpenoid triepoxide in TWHF (Kupchan et al., 1972), has been reported to exert multiple biological activities including anti-inflammatory, antifertility, antineoplastic, and immunosuppressive effects (Gu and Brandwein, 1998; Huynh et al., 2000; Shamon et al., 1997; Yang et al., 1992). Despite the various pharmacological potencies, the clinical applications of TP are limited by the narrow therapeutic window and severe toxicity in renal, hepatic, reproductive, and cardiovascular systems (Huynh et al., 2000; Li et al., 2012, 2014a, 2014b; Zhou et al., 2014).
The immunoregulatory effects of Chinese herbal medicine on the maturation and function of dendritic cells
2015, Journal of EthnopharmacologyAnti-arthritic activity of luteolin in Freund's complete adjuvant-induced arthritis in rats by suppressing P2X4 pathway
2015, Chemico-Biological InteractionsAntinociceptive and anti-inflammatory activities of Schefflera octophylla extracts
2015, Journal of EthnopharmacologyEffects and mechanisms of Geniposide on rats with adjuvant arthritis
2014, International Immunopharmacology