Protein geranylgeranylation regulates the balance between Th17 cells and Foxp3+ regulatory T cells
Protein geranylgeranylation regulates the balance between Th17 cells and Foxp3+ regulatory T cells
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DOI：
10.1093/intimm/dxp037
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发表时间：
2009-06-01
影响因子：
4.4
通讯作者：
Nakajima, Hiroshi
中科院分区：
文献类型：
--
作者：
Kagami, Shin-ichiro;Owada, Takayoshi;Nakajima, Hiroshi
最近的研究表明，他汀类药物，甲羟戊酸途径中的3-羟基-3-甲基戊二酰（HMG）-CoA还原酶的抑制剂，表现出抗炎作用。然而，他汀类药物对CD 4（+）T细胞分化的免疫调节作用及其潜在机制在很大程度上仍然未知。为了解决这些问题，我们研究了辛伐他汀和蛋白法尼基化和香叶基香叶基化抑制剂对产生IL-17的T细胞（T（h）17细胞）和Foxp 3（+）CD 4（+）T细胞分化的影响。辛伐他汀通过抑制HMG-CoA还原酶活性抑制T（h）17细胞的分化，但促进Foxp 3（+）CD 4（+）T细胞的分化。香叶基香叶基转移酶I抑制剂GGTI-298，而不是法尼基转移酶抑制剂FTI-277，模仿辛伐他汀的作用，表明蛋白质香叶基香叶基化的抑制是该作用的原因。此外，Foxp 3（+）CD 4（+）T细胞在转化生长因子-β和GGTI-298的存在下发育，在体外T细胞增殖测定以及自身免疫性结肠炎模型中充当调节性T细胞（TcB）。最后，GGTI-298诱导SOCS 3表达，并抑制IL-6诱导的CD 4（+）T细胞信号转导和转录激活因子3磷酸化。综上所述，这些结果表明，蛋白质香叶基香叶基化增强T（h）17细胞的分化，并部分地通过抑制SOCS 3表达来抑制Foxp 3（+）T细胞的分化。
Recent studies have suggested that statins, the inhibitors for 3-hydroxy-3-methyglutaryl (HMG)-CoA reductase in the mevalonate pathway, exhibit anti-inflammatory effects. However, the immune modulatory effects of statins on the differentiation of CD4(+) T cells and their underlying mechanisms are still largely unknown. To address these issues, we examined the effect of simvastatin and inhibitors for protein farnesylation and geranylgeranylation on the differentiation of IL-17-producing T cells (T(h)17 cells) and Foxp3(+) CD4(+) T cells. Simvastatin inhibited the differentiation of T(h)17 cells through the inhibition of HMG-CoA reductase activity but enhanced the differentiation of Foxp3(+) CD4(+) T cells. Geranylgeranyltransferase I inhibitor, GGTI-298, but not farnesyltransferase inhibitor, FTI-277, mimicked the effects of simvastatin, indicating that the inhibition of protein geranylgeranylation is responsible for the effects. Moreover, Foxp3(+) CD4(+) T cells developed in the presence of transforming growth factor-beta and GGTI-298 functioned as regulatory T cells (Tregs) in in vitro T cell proliferation assay as well as in an autoimmune colitis model. Finally, GGTI-298 induced SOCS3 expression and inhibited IL-6-induced signal transducers and activators of transcription3 phosphorylation in CD4(+) T cells. Taken together, these results indicate that protein geranylgeranylation enhances the differentiation of T(h)17 cells and inhibits the differentiation of Foxp3(+) Tregs partly via the inhibition of SOCS3 expression.