A cell permeable peptide inhibitor of NFAT inhibits macrophage cytokine expression and ameliorates experimental colitis.
A cell permeable peptide inhibitor of NFAT inhibits macrophage cytokine expression and ameliorates experimental colitis.
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DOI：
10.1371/journal.pone.0034172
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Plevy SE
中科院分区：
文献类型：
--
作者：
Elloumi HZ;Maharshak N;Rao KN;Kobayashi T;Ryu HS;Mühlbauer M;Li F;Jobin C;Plevy SE
活化T细胞核因子（NFAT）在免疫和非免疫细胞的发育和功能中起着关键作用。虽然NFAT是T细胞细胞因子的中心转录调节因子，但其在巨噬细胞特异性基因表达中的作用尚不明确。我们小组以前的工作表明，NFAT调节巨噬细胞中的Il 12 b基因表达。在这里，我们进一步研究了小鼠巨噬细胞中的NFAT功能，并确定了细胞渗透性NFAT抑制剂肽11 R-VIVIT对小鼠实验性结肠炎的影响。用他克莫司或11 R-VIVIT处理骨髓源性巨噬细胞（BMDM）显著抑制LPS和LPS + IFN-γ诱导的IL-12 p40 mRNA和蛋白表达。IL-12 p70和IL-23分泌也减少。NFAT核转位和与IL-12 p40启动子的结合通过NFAT抑制而减少。在IL-10缺陷（IL-10 −/−）小鼠的BMDM中进行的实验表明，11 R-VIVIT对IL-12表达的抑制与IL-10表达无关。为了测试其治疗潜力，将11 R-VIVIT全身给予患有吡罗昔康诱导的结肠炎的Il 10 −/−小鼠。与用无活性肽处理的小鼠相比，11 R-VIVIT处理的小鼠显示结肠炎的显著改善。此外，减少自发分泌的IL-12 p40和TNF在上清液中从结肠外植体培养物被证明。总之，NFAT在T细胞生物学中的作用被广泛认可，也调节巨噬细胞中重要的先天性炎症通路。通过细胞渗透性抑制肽选择性阻断NFAT是治疗炎症性肠病的有前景的治疗策略。
Nuclear factor of activated T cells (NFAT) plays a critical role in the development and function of immune and non-immune cells. Although NFAT is a central transcriptional regulator of T cell cytokines, its role in macrophage specific gene expression is less defined. Previous work from our group demonstrated that NFAT regulates Il12b gene expression in macrophages. Here, we further investigate NFAT function in murine macrophages and determined the effects of a cell permeable NFAT inhibitor peptide 11R-VIVIT on experimental colitis in mice. Treatment of bone marrow derived macrophages (BMDMs) with tacrolimus or 11R-VIVIT significantly inhibited LPS and LPS plus IFN-γ induced IL-12 p40 mRNA and protein expression. IL-12 p70 and IL-23 secretion were also decreased. NFAT nuclear translocation and binding to the IL-12 p40 promoter was reduced by NFAT inhibition. Experiments in BMDMs from IL-10 deficient (Il10 −/−) mice demonstrate that inhibition of IL-12 expression by 11R-VIVIT was independent of IL-10 expression. To test its therapeutic potential, 11R-VIVIT was administered systemically to Il10 −/− mice with piroxicam-induced colitis. 11R-VIVIT treated mice demonstrated significant improvement in colitis compared to mice treated with an inactive peptide. Moreover, decreased spontaneous secretion of IL-12 p40 and TNF in supernatants from colon explant cultures was demonstrated. In summary, NFAT, widely recognized for its role in T cell biology, also regulates important innate inflammatory pathways in macrophages. Selective blocking of NFAT via a cell permeable inhibitory peptide is a promising therapeutic strategy for the treatment of inflammatory bowel diseases.
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影响因子：
64.5
作者：
LIU, J;FARMER, JD;SCHREIBER, SL
通讯作者：
SCHREIBER, SL
影响因子：
4.8
作者：
Hirotani, H;Tuohy, NA;Clipstone, NA
通讯作者：
Clipstone, NA
在人类天然杀伤细胞中，活化T细胞NFATP和NFATC的核因子的激活和表达：CD16配体结合时调节。
DOI：
10.1084/jem.182.3.801
发表时间：
1995-09-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Aramburu J;Azzoni L;Rao A;Perussia B
通讯作者：
Perussia B
DOI：
10.1084/jem.20051047
发表时间：
2005-12-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hegazi RA;Rao KN;Mayle A;Sepulveda AR;Otterbein LE;Plevy SE
通讯作者：
Plevy SE
影响因子：
4.4
作者：
Karrasch, Thomas;Kim, Joo-Sung;Jobin, Christian
通讯作者：
Jobin, Christian