Oncostatin M-Induced and Constitutive Activation of the JAK2/STAT5/CIS Pathway Suppresses CCL1, but Not CCL7 and CCL8, Chemokine Expression
Oncostatin M-Induced and Constitutive Activation of the JAK2/STAT5/CIS Pathway Suppresses CCL1, but Not CCL7 and CCL8, Chemokine Expression
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DOI：
10.4049/jimmunol.181.10.7341
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发表时间：
2008-11-15
影响因子：
4.4
通讯作者：
Hermanns, Heike M.
中科院分区：
文献类型：
--
作者：
Hintzen, Christoph;Haan, Claude;Hermanns, Heike M.
白细胞向受伤组织的募集对于炎症反应的启动以及对抗肿瘤进展的免疫监视至关重要。在这项研究中，我们发现，作为il -6型细胞因子家族的一员和强效的促炎细胞因子，oncostatin M能以比11,413或tnf - α更快的速度刺激人真皮成纤维细胞中趋化因子CCL1、CCL7和CCL8的表达。CCL1的产生。CCL8对单核细胞的迁移很重要，而针对CCL1的特异性抗体还能抑制T淋巴细胞的迁移。我们发现丝裂原活化蛋白激酶ERKI/2和p38是CCL1和CCL8表达增强的关键因素。ERKI/2靶基因c-Jun或c-Fos的缺失显著降低了CCL1和CCL8的表达，而p38 NUPK通过抑制三四丙氨酸延长了CCL1、CCL7和CCL8 mRNA的半衰期。STAT转录因子STAT1、STAT3或STAT5均不刺激CCL1或CCL8的转录。然而，我们发现激活的STAT5对CCL1基因表达具有负调控功能。重要的是，STAT5对CCL1表达的抑制作用并不需要STAT5本身，而是需要其靶基因细胞因子诱导的含有sh2结构域的蛋白。最后，我们发现通过JAK2突变形式（JAK2 V617F）在骨髓增殖性疾病患者中发生的STATS的组成性激活类似地抑制CCL1的表达。综上所述，我们确定了OSM新的重要炎症靶基因，这些基因本身独立于STAT信号传导，但依赖于MAPK的激活，并通过细胞因子诱导的sh2结构域蛋白的stat5依赖性表达部分抑制。中华免疫学杂志，2008,18(1):741 - 749。
The recruitment of leukocytes to injured tissue is crucial for the initiation of inflammatory responses as well as for immune surveillance to fight tumor progression. In this study, we show that oncostatin M, a member of the IL-6-type cytokine family and potent proinflammatory cytokine stimulates the expression of the chemokines CCL1, CCL7, and CCL8 in primary human dermal fibroblasts at a faster kinetic than 11,413 or TNF-alpha. The production of CCL1. and CCL8 is important for migration of monocytes, while specific Abs against CCL1 additionally inhibit the migration of T lymphocytes. We identify the mitogen-activated protein kinases ERKI/2 and p38 as crucial factors for the enhanced expression of CCL1 and CCL8. Depletion of the ERKI/2 target genes c-Jun or c-Fos strongly decrease CCL1 and CCL8 expression, while p38 NUPK prolongs the half-life of CCL1, CCL7, and CCL8 mRNA through inhibition of tristetraprolin. None of the STAT transcription factors STAT1, STAT3, or STAT5 stimulate transcription of CCL1 or CCL8. However, we identify a negative regulatory function of activated STAT5 for the gene expression of CCL1. Importantly, not STAT5 itself, but its target gene cytokine inducible SH2-domain containing protein is required for the STAT5 inhibitory effect on CCL1 expression. Finally, we show that constitutive activation of STATS through a mutated form of JAK2 (JAK2 V617F) occurring in patients with myeloproliferative disorders similarly suppresses CCL1 expression. Taken together, we identify novel important inflammatory target genes of OSM which are independent of STAT signaling per se, but depend on MAPK activation and are partly repressed through STAT5-dependent expression of cytokine inducible SH2-domain containing protein. The Journal of Immunology, 2008, 181: 7341-7349.