Saouaf Sandra J, Li Bin, Zhang Geng, Shen Yuan, Furuuchi Narumi, Hancock Wayne W, Greene Mark I
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104-6082, USA.
Exp Mol Pathol. 2009 Oct;87(2):99-104. doi: 10.1016/j.yexmp.2009.06.003. Epub 2009 Jul 3.
Collagen-induced arthritis (CIA) is an established mouse model of disease with hallmarks of clinical rheumatoid arthritis. Histone/protein deacetylase inhibitors (HDACi) are known to inhibit the pathogenesis of CIA and other models of autoimmune disease, although the mechanisms responsible are unclear. Regulatory T cell (Treg) function is defective in rheumatoid arthritis. FOXP3 proteins in Tregs are present in a dynamic protein complex containing histone acetyltransferase and HDAC enzymes, and FOXP3 itself is acetylated on lysine residues. We therefore investigated the effects of HDACi therapy on regulatory T cell function in the CIA model. Administration of an HDACi, valproic acid (VPA), significantly decreased disease incidence (p<0.005) and severity (p<0.03) in CIA. In addition, VPA treatment increased both the suppressive function of CD4(+)CD25(+) Tregs (p<0.04) and the numbers of CD25(+)FOXP3(+) Tregs in vivo. Hence, clinically approved HDACi such as VPA may limit autoimmune disease in vivo through effects on the production and function of FOXP3(+) Treg cells.
胶原诱导性关节炎（CIA）是一种公认的具有临床类风湿性关节炎特征的疾病小鼠模型。已知组蛋白/蛋白质脱乙酰酶抑制剂（HDACi）可抑制CIA及其他自身免疫性疾病模型的发病机制，但其具体机制尚不清楚。类风湿性关节炎中调节性T细胞（Treg）功能存在缺陷。Tregs中的FOXP3蛋白存在于一种动态蛋白质复合物中，该复合物包含组蛋白乙酰转移酶和HDAC酶，并且FOXP3自身在赖氨酸残基上被乙酰化。因此，我们研究了HDACi疗法对CIA模型中调节性T细胞功能的影响。给予HDACi丙戊酸（VPA）可显著降低CIA的疾病发病率（p<0.005）和严重程度（p<0.03）。此外，VPA治疗可增强体内CD4(+)CD25(+) Tregs的抑制功能（p<0.04）以及CD25(+)FOXP3(+) Tregs的数量。因此，临床上已批准的HDACi如VPA可能通过影响FOXP3(+) Treg细胞的产生和功能来限制体内自身免疫性疾病。
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