Analysis of expression of FLI1 and MMP1 in American cutaneous leishmaniasis caused by Leishmania braziliensis infection.
Analysis of expression of FLI1 and MMP1 in American cutaneous leishmaniasis caused by Leishmania braziliensis infection.
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DOI：
10.1016/j.meegid.2017.01.018
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发表时间：
2017-04
期刊：
影响因子：
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通讯作者：
Castellucci LC
中科院分区：
文献类型：
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作者：
Almeida L;Silva JA;Andrade VM;Machado P;Jamieson SE;Carvalho EM;Blackwell JM;Castellucci LC
FlI1(Friend白血病病毒整合1)和IL6(IL-6；IL-6)与巴西利什曼原虫易感性相关。皮肤病变表现为基质金属蛋白酶1(MMP1)的过度表达。在其他皮肤病中，FLI1启动子甲基化降低了FLI1的表达，低FLI1下调了MMP1的表达。IL-6可增加FLI1的表达。我们推测皮肤利什曼病中FLI1的表观遗传调控与IL-6一起可能决定了MMP1的表达。虽然通常较低(10%)，但病变活检组织中Fl1启动子甲基化百分比低于正常皮肤(P=0.001)。与预期相反，在皮损(r=0.98，P=0.0005)和IL-6处理的巴西乳杆菌感染的巨噬细胞(r=0.99，P=0.0004)中，Fli 1甲基化与基因表达呈显著正相关。在计算机分析中，对Fl1启动子的分析显示，H3K27ac和抑制DNA甲基化标记共同存在，以增强基因表达。未处理(P=0.0002)和IL-6处理(P=0.028)的巨噬细胞在感染后3~24小时内Fli-1表达增强。MMP1在病变组织中增强(P=0.0002)，在感染的巨噬细胞中诱导(P=0.007)，但被IL-6强烈抑制。在皮损或感染的巨噬细胞(加/不加IL-6)中，FLI1和MMP1的表达之间没有相关性。结论：MMP1受FLI1以外的其他因素的调节，IL-6对MMP1的影响与其对FLI1的影响无关。
FLI1 (Friend leukemia virus integration 1) and IL6 (interleukin 6; IL-6) are associated with Leishmania braziliensis susceptibility. Cutaneous lesions show exaggerated matrix metalloproteinase 1 (MMP1). In other skin diseases, FLI1 promoter methylation reduces FLI1 expression, and low FLI1 down-regulates MMP1. IL-6 increases FLI1 expression. We hypothesized that epigenetic regulation of FLI1 in cutaneous leishmaniasis, together with IL-6, might determine MMP1 expression. While generally low (<10%), percent FLI1 promoter methylation was lower (P=0.001) in lesion biopsies than normal skin. Contrary to expectation, a strong positive correlation occurred between FLI1 methylation and gene expression in lesions (r=0.98, P=0.0005) and in IL-6-treated L. braziliensis-infected macrophages (r=0.99, P=0.0004). In silico analysis of the FLI1 promoter revealed co-occurring active H3K27ac and repressive DNA methylation marks to enhance gene expression. FLI1 expression was enhanced between 3 and 24 hours post infection in untreated (P=0.0002) and IL-6-treated (P=0.028) macrophages. MMP1 was enhanced in lesion biopsies (P=0.0002), induced (P=0.007) in infected macrophages, but strongly inhibited by IL-6. No correlations occurred between FLI1 and MMP1 expression in lesions or infected macrophages (with/without IL-6). We conclude that MMP1 is regulated by factors other than FLI1, and that the influence of IL-6 on MMP1 was independent of its effect on FLI1.