Effective therapy for nephritis in (NZB × NZW)F1 mice with triptolide and tripdiolide, the principal active components of the Chinese herbal remedyTripterygium wilfordii Hook F

Autor: Chun Y. Gao, Patricia M. Zerfas, Nancy S. Longo, Fred Fan, Xuelian Tao, Victoria Hoffmann, Peter E. Lipsky
Rok vydání: 2008
Předmět:
Zdroj: Arthritis & Rheumatism. 58:1774-1783
ISSN: 1529-0131
0004-3591
Popis: Extracts of the Chinese antirheumatic herbal remedy Tripterygium wilfordii Hook F (TWHF) have been shown to be of therapeutic benefit in patients with a variety of autoimmune and inflammatory diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and psoriasis (1). Although TWHF has toxic potential, careful extraction procedures have generated preparations with an acceptable frequency of adverse reactions, which are largely related to the gastrointestinal tract and amenorrhea (1). Although the extracts of TWHF contain a variety of components, including diterpenoids, triterpenoids, and alkaloids, evidence suggests that most, if not all, of the therapeutic activity of extracts of TWHF can be accounted for by the content of 2 diterpenoids, triptolide and tripdiolide (2). However, it has been assumed that individual components do not work as well as the extracts because of unknown effects of mixtures of components. For example, one open clinical study compared triptolide with an ethyl acetate (EA) extract of TWHF in the treatment of RA and reported that triptolide was less effective in improving clinical manifestations of the disease and was associated with more side effects than the extract of TWHF (3). Despite the belief in a synergistic benefit from mixtures of components of TWHF extracts, investigation into the biologic activities of individual constituents of TWHF has proceeded. As one of the major active components of TWHF, triptolide has been reported to be able to suppress the production of a wide range of proinflammatory cytokines, including interleukin-2 (IL-2), interferon-γ (IFNγ), IL-6, and tumor necrosis factor (TNF), as well as inhibit the up-regulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) (4,5). Previous studies have shown that triptolide exerts its anti-inflammatory and immunosuppressive actions by directly suppressing the transcription of the genes that encode these proteins through interference with the function of transcription factors such as NF-κB, activator protein 1, nuclear factor of activated T cells, and Oct-1 (6–8). The immunosuppressive and anti-inflammatory activities of extracts of TWHF have been documented in several animal models, including collagen-induced arthritis (CIA) in mice and the air-pouch model of carageenan-induced inflammation in rats (9,10), whereas triptolide has been shown to suppress CIA when given prophylactically (11) or after the onset of disease (12). Moreover, triptolide has been claimed to be effective in the treatment of RA and psoriasis, although this has not been documented in randomized clinical trials (3,13), and the therapeutic effect in RA may be lower than that of the extract of TWHF (3). Structurally, tripdiolide is similar to triptolide, with an α,β-unsaturated lactone ring and 3 epoxide adducts. The only difference is that the hydrogen at the C2 position of triptolide is replaced by a hydroxide group in tripdiolide. Previous studies have shown that tripdiolide is as potent as triptolide in suppressing in vitro cell proliferation and IL-2 production by mitogenstimulated T cells (2). Only 1 study tested the in vivo biologic activity of tripdiolide, and prolonged survival in leukemia-bearing mice as a result of treatment with tripdiolide was reported (14). However, the impact of tripdiolide on animal models of autoimmunity or inflammation has not been examined. Previously, studies have shown that 2 extracts of TWHF improved the clinical manifestations of lupus in MRL/lpr mice (15,16). However, the composition of these extracts was not examined. In addition, the extracts were used prophylactically to prevent disease development but were not active as a therapy for established disease. Recently, we used the EA extract of TWHF in the treatment of established lupus nephritis in (NZB X NZW)F1 mice and found significant amelioration of disease activity (17). No previous study has examined the impact of purified components of TWHF on animal models of lupus nephritis. The current study was therefore performed to evaluate the therapeutic effects of the 2 individual diterpenoids on established nephritis in the (NZB X NZW)F1 mouse. We found that renal disease remarkably improved, and there was greater survival of (NZB X NZW)F1 mice treated with either triptolide or tripdiolide than mice treated with vehicle. These results support the conclusions that the therapeutic value of extracts of TWHF in lupus nephritis can be accounted for by the triptolide and tripdiolide contents, that cooperation between components is not required for therapeutic benefit, and that either diterpenoid could be effective therapy for lupus nephritis.
Databáze: OpenAIRE
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