银屑病
哈卡特
伊米奎莫德
炎症
肿瘤坏死因子α
钙泊三醇
MAPK/ERK通路
p38丝裂原活化蛋白激酶
医学
免疫学
癌症研究
角质形成细胞
药理学
激酶
化学
体外
生物
细胞生物学
生物化学
作者
Zheng Lin,Meng Ma,Heng Li,Qing Qi,Yuting Liu,Yu-xi Yan,Yunfu Shen,Xiaoqian Yang,Fenghua Zhu,Shijun He,Wei Tang,Jian‐Ping Zuo
标识
DOI:10.1016/j.phrs.2017.11.012
摘要
DZ2002, a reversible S-adenosyl-l-homocysteine hydrolase (SAHH) inhibitor with immunosuppressive properties and potent therapeutic activity against various autoimmune diseases in mice. The present study was designed to characterize the potential therapeutic effects of DZ2002 on murine model of psoriasis and reveal the correlated mechanisms. In this report, we demonstrated that in vitro, DZ2002 significantly decreased the expression of pro-inflammatory cytokines and adhesion molecule including IL-1α, IL-1β, IL-6, IL-8, TNF-α and ICAM-1 by inhibiting the phosphorylation of p38 MAPK, ERK and JNK in TNF-α/IFN-γ-stimulated HaCaT human keratinocytes. Topical administration of DZ2002 alleviated the imiquimod (IMQ)-induced psoriasis-like skin lesions and inflammation in mice, the therapeutic effect was comparable with the Calcipotriol. Moreover, the inflammatory skin disorder was restored by DZ2002 treatment characterized by reducing both of the CD3+ T cell accumulation and the psoriasis-specific cytokines expression. Further, we found that DZ2002 improved IMQ-induced splenomegaly and decreased the frequency of splenic IL-17-producing T cells. Our finding offered the convincing evidence that SAHH inhibitor DZ2002 might attenuate psoriasis by simultaneously interfering the abnormal activation and differentiation of keratinocytes and accumulation of IL-17-producing T cells in skin lesions.
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