IL-2 Inhibition of Th17 Generation Rather Than Induction of Treg Cells Is Impaired in Primary Sjögren's Syndrome Patients.
IL-2 Inhibition of Th17 Generation Rather Than Induction of Treg Cells Is Impaired in Primary Sjögren's Syndrome Patients.
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原发性干燥综合征患者中 IL-2 对 Th17 生成的抑制作用而非 Treg 细胞的诱导作用受到损害
DOI：
10.3389/fimmu.2018.01755
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发表时间：
2018
影响因子：
7.3
通讯作者：
Dong L
中科院分区：
文献类型：
--
作者：
Luo J;Ming B;Zhang C;Deng X;Li P;Wei Z;Xia Y;Jiang K;Ye H;Ma W;Liu Z;Li H;Yang XP;Dong L
目的探讨IL-2在原发性干燥综合征（pSS）患者Th 17/Th 2平衡中的作用，并阐明其诱导Th 17分化的机制。本研究涉及31例pSS患者、7例Sicca患者和31例健康受试者。流式细胞术检测Th 17和Treg细胞，免疫组化检测IL-17 A。通过ELISA和qPCR评估IL-2和IL-6水平。采用免疫组织化学和流式细胞术检测唾液腺中p-STAT 5和p-STAT 3的表达。通过染色质免疫沉淀法测量STAT 5和STAT 3与Il 17 a基因座的结合。我们发现，与健康受试者相比，pSS患者外周和SG中Th 17细胞的百分比增加，但Treg细胞没有变化。同时，pSS患者血浆IL-2水平降低，IL-6和IL-17 A水平升高。IL-2/IL-6比值降低，IL-2水平与IL-17 A水平呈负相关。IL 6和IL 17 a mRNA的表达显著增加，而Foxp 3、Tgfb 1、Tnfa和Ifng mRNA的表达相当。此外，在pSS患者的SG和外周CD 4 + T细胞中，STAT 5磷酸化水平（p-STAT 5）降低，p-STAT 3增强。体外IL-2处理诱导的STAT 5与STAT 3竞争结合人IL 17 a基因座，导致Th 17分化减少，这与转录激活标记物H3 K4 me 3减少有关。我们的研究结果表明，Treg的非依赖性上调的Th 17产生的pSS，这可能是由于缺乏IL-2介导的抑制Th 17分化。本研究确定了IL-2介导的pSS免疫抑制的新机制。
To investigate the role of IL-2 in the balance of Th17 and Tregs and elucidate the underlying mechanisms of enhanced Th17 differentiation in primary Sjögren’s syndrome (pSS) patients. This study involved 31 pSS patients, 7 Sicca patients, and 31 healthy subjects. Th17 and Treg cells were determined by flow cytometry, and IL-17A was detected by immunohistochemistry. IL-2 and IL-6 levels were assessed by ELISA and qPCR. p-STAT5 and p-STAT3 in salivary glands (SGs) were evaluated by immunohistochemistry and flow cytometry. The binding of STAT5 and STAT3 to the Il17a gene locus was measured by chromatin immunoprecipitation. We found that the percentage of Th17 cells was increased in the periphery and SG of pSS patients when compared with healthy subjects, but the Treg cells was unchanged. Meanwhile, the IL-2 level was reduced, and the IL-6 and IL-17A level was increased in the plasma of pSS patients. The ratio of IL-2 and IL-6 level was also decreased and IL-2 level was negatively correlated with the level of IL-17A. The expression of Il6 and Il17a mRNA was significantly increased, whereas Foxp3, Tgfb1, Tnfa, and Ifng mRNA were comparable. Furthermore, the level of STAT5 phosphorylation (p-STAT5) was reduced and p-STAT3 was enhanced in the SGs and in peripheral CD4+ T cells of pSS patients. In vitro IL-2 treatment-induced STAT5 competed with STAT3 binding in human Il17a locus, leading to decreased Th17 differentiation, which was associated with the reduced transcription activation marker H3K4me3. Our findings demonstrated a Treg-independent upregulation of Th17 generation in pSS, which is likely due to a lack of IL-2-mediated suppression of Th17 differentiation. This study identified a novel mechanism of IL-2-mediated immune suppression in pSS.
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DOI：
10.4049/jimmunol.1490019
发表时间：
2014-06-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Rosenberg SA
通讯作者：
Rosenberg SA
影响因子：
--
作者：
Maiti, Amit K.;Kim-Howard, Xana;Viswanathan, Parvathi;Guillen, Laura;Rojas-Villarraga, Adriana;Deshmukh, Harshal;Direskeneli, Haner;Saruhan-Direskeneli, Gueher;Canas, Carlos;Tobon, Gabriel J.;Sawalha, Amr H.;Chernavsky, Alejandra C.;Anaya, Juan-Manuel;Nath, Swapan K.
通讯作者：
Nath, Swapan K.
影响因子：
12.8
作者：
Gottenberg, JE;Lavie, F;Mariette, X
通讯作者：
Mariette, X
DOI：
10.1084/jem.20111174
发表时间：
2012-02-13
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Johnston RJ;Choi YS;Diamond JA;Yang JA;Crotty S
通讯作者：
Crotty S
影响因子：
5.5
作者：
Bikker, Angela;Moret, Frederique M.;van Roon, Joel A. G.
通讯作者：
van Roon, Joel A. G.