Haplotype-independent costimulation of IL-10 secretion by SDF-1/CXCL12 proceeds via AP-1 binding to the human IL-10 promoter
Haplotype-independent costimulation of IL-10 secretion by SDF-1/CXCL12 proceeds via AP-1 binding to the human IL-10 promoter
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DOI：
10.4049/jimmunol.178.3.1581
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发表时间：
2007-02-01
影响因子：
4.4
通讯作者：
Hedin, Karen E.
中科院分区：
文献类型：
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作者：
Kremer, Kimberly N.;Kumar, Ashok;Hedin, Karen E.
趋化因子，基质细胞衍生因子-1（SDF-1）/CXCL 12的共刺激已被证明可增加TCR刺激的人T细胞分泌的IL-10的量;然而，这种反应的分子机制尚不清楚。这一信号通路的知识可能是有用的，因为大量的证据表明，缺乏IL-10分泌促进自身免疫。人IL-10基因座是高度多态性的。我们在这项研究中报告，SDF-1共刺激IL-10分泌的T细胞含有所有三种最常见的人类IL-10启动子单倍型，确定单核苷酸多态性在-1082，-819，和-592 bp（编号是相对于转录起始位点）。我们进一步表明，SDF-1主要共刺激IL-10分泌的一个不同的群体的CD 45 RA-（“记忆”）表型T细胞，包括细胞表达sususumedIL-10分泌的一个不同的群体的CD 45 RA（-）（“记忆”）表型T细胞，包括细胞表达假定的调节性T细胞标志物，Foxp 3。为了解决这种反应的分子机制，我们表明，SDF-1共刺激转录活性在正常人T细胞的报告质粒含有1.1 kb的所有三个常见的IL-10启动子单倍型。通过突变AP-1转录因子的两个非多态性结合位点来消除IL-10启动子活性，并且原代人T细胞的染色质免疫沉淀试验显示SDF-1共刺激增强AP-1与这两个位点的结合。总之，这些结果描绘了负责SDF-1共刺激T细胞IL-10分泌的分子机制。因为它在几种人类单倍型和包括Foxp 3（+）T细胞在内的不同T细胞群体中被保留，所以IL-10调节的这种途径可能代表了调节这种重要的免疫调节细胞因子表达的关键机制。
Costimulation by the chemokine, stromal cell-derived factor-1 (SDF-1)/CXCL12, has been shown to increase the amount of IL-10 secreted by TCR-stimulated human T cells; however, the molecular mechanisms of this response are unknown. Knowledge of this signaling pathway may be useful because extensive evidence indicates that deficient IL-10 secretion promotes autoimmunity. The human IL-10 locus is highly polymorphic. We report in this study that SDF-1 costimulates IL-10 secretion from T cells containing all three of the most common human IL-10 promoter haplotypes that are identified by single-nucleotide polymorphisms at - 1082, -819, and -592 bp (numbering is relative to the transcription start site). We further show that SDF-1 primarily costimulates IL-10 secretion by a diverse population of CD45RA- ("memory") phenotype T cells that includes cells expressing the presumedIL-10 secretion by a diverse population of CD45RA(-) ("memory") phenotype T cells that includes cells expressing the presumed regulatory T cell marker, Foxp3. To address the molecular mechanisms of this response, we showed that SDF-1 costimulates the transcriptional activities in normal human T cells of reporter plasmids containing 1.1 kb of all three of the common IL-10 promoter haplotypes. IL-10 promoter activity was ablated by mutating two nonpolymorphic binding sites for the AP-1 transcription factor, and chromatin immunoprecipitation assays of primary human T cells revealed that SDF-1 costimulation enhances AP-1 binding to both of these sites. Together, these results delineate the molecular mechanisms responsible for SDF-1 costimulation of T cell IL-10 secretion. Because it is preserved among several human haplotypes and in diverse T cell populations including Foxp3(+) T cells, this pathway of IL-10 regulation may represent a key mechanism for modulating expression of this important immunoregulatory cytokine.