Effective therapy for nephritis in (NZB x NZW)F1 mice with triptolide and tripdiolide, the principal active components of the Chinese herbal remedy Tripterygium wilfordii Hook F.
OBJECTIVE
Triptolide and tripdiolide are thought to be active components of the Chinese antirheumatic herbal remedy Tripterygium wilfordii Hook F, which has been shown to be effective in treating murine lupus nephritis. This study was undertaken to examine the therapeutic effect of triptolide and tripdiolide on established lupus nephritis in (NZB x NZW)F1 mice.


METHODS
(NZB x NZW)F1 mice were treated with vehicle, triptolide, or tripdiolide for 15 weeks beginning at the age of 29 weeks (after the development of lupus nephritis). Body weight, proteinuria, and anti-double-stranded DNA (anti-dsDNA) antibodies were monitored, and the kidney and spleen were assessed histologically. Culture supernatants of spleen mononuclear cells were assayed for cytokines.


RESULTS
By 28 weeks, most (NZB x NZW)F1 mice had developed lupus nephritis. Vehicle-treated mice exhibited progressive proteinuria, hypoalbuminemia, elevated blood urea nitrogen (BUN) levels, and evidence of severe nephritis. In contrast, proteinuria and BUN levels were significantly reduced in mice treated with either triptolide or tripdiolide as compared with those treated with vehicle. There was no hypoalbuminemia or apparent evidence of lupus nephritis in mice treated with either of the 2 diterpenoids. At 44 weeks of age, the survival rate in mice treated with vehicle (35.7%) was markedly lower than that in mice treated with either triptolide (87.5%) or tripdiolide (88.2%). The mean level of anti-dsDNA antibody in mice treated with tripdiolide was lower than that in the vehicle-treated mice upon completion of the treatment course. Production of tumor necrosis factor, interleukin-6, and monocyte chemoattractant protein 1 by spleen cells was also decreased after diterpenoid therapy.


CONCLUSIONS
Therapy with triptolide or tripdiolide significantly ameliorated lupus nephritis in (NZB x NZW)F1 mice, reduced cytokine and chemokine production, and prolonged survival.
Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD 20892, USA.
Xuelian
X
Tao
Fred
F
Fan
Victoria
V
Hoffmann
Chun Y
CY
Gao
Nancy S
NS
Longo
Patricia
P
Zerfas
Peter E
PE
Lipsky
D000818:Animals; D004195:Disease Models, Animal; D004224:Diterpenes / Q000627:therapeutic use*; D004365:Drugs, Chinese Herbal / Q000627:therapeutic use*; D004852:Epoxy Compounds / Q000627:therapeutic use; D005260:Female; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008181:Lupus Nephritis / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D010616:Phenanthrenes / Q000627:therapeutic use*; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D029757:Tripterygium / Q000737:chemistry*
D004224:Diterpenes; D004365:Drugs, Chinese Herbal; D004852:Epoxy Compounds; D007166:Immunosuppressive Agents; D010616:Phenanthrenes; C001899:triptolide; C001898:tripdiolide