Stephanthraniline A suppressed CD4⁺ T cell-mediated immunological hepatitis through impairing PKCθ function

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• 作者：Feng-Yang Chen^a ; ^b ; Li-Fei Zhou^c ; Xiao-Yu Li^b ; Jia-Wen Zhao^b ; Shi-Fang Xu^b ; Wen-Hai Huang^b ; Li-Juan Gao^b ; Shu-Juan Hao^b ; Yi-Ping Ye^b ; ^{yeyiping2005@163.com" class="auth_mail" title="E-mail the corresponding author} ; Hong-Xiang Sun^a ; ^{sunhx@zju.edu.cn" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Stephanthraniline A (PubChem CID ; 102482096) ; Cyclosporine A (PubChem CID ; 5284373)
• 刊名：European Journal of Pharmacology
• 出版年：2016
• 出版时间：15 October 2016
• 年：2016
• 卷：789
• 期：Complete
• 页码：370-384
• 全文大小：3677 K

文摘

Stephanthraniline A (STA), a C₂₁ steroid isolated from Stephanotis mucronata (Blanco) Merr., was previously shown to inhibit T cells activation and proliferation in vitro and in vivo. The purpose of this study was to further evaluate the in vivo immunosuppressive activity of STA and to elucidate its potential mechanisms. The results showed that pretreatment with STA significantly attenuated concanavalin A (Con A)-induced hepatitis and reduced CD4⁺ T cells activation and aggregation in hepatic tissue in mice. STA directly suppressed the activation and proliferation of Con A-induced CD4⁺ T cells, and inhibited NFAT, NFκB and MAPK signaling cascades in activated CD4⁺ T cells in vitro. Moreover, it was proved that STA inhibited T cells activation and proliferation through proximal T cell-receptor (TCR) signaling- and Ca²⁺ signaling-independent way. The molecular docking studies predicted that STA could tight bind to PKCθ via five hydrogen. The further findings indicated STA directly inhibited PKCθ kinase activity, and its phosphorylation in activated CD4⁺ T cells in vitro. Collectively, the present study indicated that STA could protect against CD4⁺ T cell-mediated immunological hepatitis in mice through PKCθ and its downstream NFAT, NFκB and MAPK signaling cascades. These results highlight the potential of STA as an effective leading compound for use in the treatment of CD4⁺ T cell-mediated inflammatory and autoimmune diseases.