Effects of Zingiber officinale extract on collagen-induced arthritis in mice and IL-1 beta-induced inflammation in human synovial fibroblasts

Abstract

Ginger (Zingiber officinale Roscoe) is one of the most commonly used medicinal plants and is extensively used for the treatment of arthritic patients in Traditional Korean Medicine (TKM) due to its various pharmacological properties. In this study, we evaluated the therapeutic effects of ginger on rheumatoid arthritis (RA), particularly focusing on the regulation of Th1, Th2, and Th17 cytokines and the inhibition of matrix metalloproteinase (MMP) release in mice with collagen-induced arthritis (CIA) and primary synovial fibroblasts. RA was induced in male DBA/1J mice via immunization with type II collagen (CII). A ginger extract was prepared in water. The ginger extract (100 and 200 mg/kg) or Mobic (50 mg/kg), as a reference drug, was orally administered to CIA mice once daily for 14 days after arthritis induction. Primary fibroblasts were isolated from the synovial tissues of osteoarthritis patients and then were stimulated with IL-1 and treated with the ginger extract at different concentrations. IL-4, IFN-gamma, and IL-17 levels were measured in the serum or spleen and paw tissues of CIA mice and culture media via enzyme-linked immunosorbent assay (ELISA). The mRNA expression of IL-17, MMP-1, MMP-3, and MMP-13 was also detected in paw tissues and synovial fibroblasts through reverse transcription polymerase chain reaction (RT-PCR). Histological changes in the knee joints were observed via hematoxylin and eosin (H&E) and safranin-O staining. The major compounds in the ginger extract were analyzed using high-performance liquid chromatography (HPLC). Treatment with the ginger extract at 100 or 200mg/kg significantly decreased the levels of IL-4, IFN-gamma, and IL-17 and inhibited the expression of IL-17 in the spleen and paw tissues of CIA mice. Ginger extract inhibited the expression of MMP-1, MMP-3, and MMP-13 in the paw tissues of CIA mice and reduced inflammatory bone destruction in joint tissues. In IL-1 beta-stimulated synovial fibroblasts, the ginger extract significantly decreased the production of IFN-gamma and IL-17 via inhibition of mRNA expression. The ginger extract also suppressed the expression of MMP-1, MMP-3, and MMP-13 mRNA. Vanillylacetone, 6-gingerol, 6-shogaol, and 1,4-cineol were identified as the main compounds in the ginger extract. These results indicate that ginger can prevent RA progression by inhibiting the secretion of Th1/Th2 and Th17 cytokines and MMPs, which are involved in the pathogenesis of RA.