科研之友
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摘要
Lck, one of the Src family protein tyrosine kinases, plays a critical role in T-cell receptor-induced signaling that leads to T-cell activation, proliferation and differentiation. Interruption of the molecular interaction through the lck SH2 domain blocks T-cell activation and subsequent proliferation. Previously, we demonstrated that rosmarinic acid (RosA), an lck SH2 domain inhibitor, suppresses T-cell function via dual mechanism such as inhibition of T-cell activation and lck-dependent apoptosis induction. RosA alleviated arthritis in Collagen-Induced Arthritis (CIA) model but a fairly high amount of RosA was required. To overcome this problem, we generated various kinds of C-terminus modified RosA analogues and found a methyl ester derivative of RosA (RosA-Me) to have the most improved inhibition activity in IL-2 promoter analysis and T-cell proliferation assay. The objective of this study was to assess the anti-arthritic activity of RosA-Me compared to the parent compound RosA and Methotrexate (MTX) in a murine CIA model. Compared to vehicle, treatment of mice with RosA-Me (50 mg kg(-1) day(-1), i.p.) greatly reduced the inflammation indexes which suggests RosA-Me has better in vivo anti-rheumatoid arthritis activity acquired maybe from the stronger cell penetrating ability. Thus, our studies suggest that RosA-Me is a RosA derivative with a potent anti-arthritic effect in CIA, through its combined immunosuppressive and anti-inflammatory actions.
- 出版日期2015-4-1
