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首页> 外文期刊>Cytokine >Selective JAK/STAT3 signalling regulates transcription of colony stimulating factor-2 and -3 in Concanavalin-A-activated mesenchymal stromal cells
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Selective JAK/STAT3 signalling regulates transcription of colony stimulating factor-2 and -3 in Concanavalin-A-activated mesenchymal stromal cells

机译：选择性JAK / STAT3信号传导调节伴刀豆球蛋白A激活的间充质基质细胞中集落刺激因子2和-3的转录

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摘要

Human bone marrow-derived mesenchymal stromal cells (MSCs) express Toll-like receptors (TLRs) and produce cytokines and chemokines, all of which contribute to these cells' immunomodulatory and proangiogenic properties. Among the secreted cytokines, colony-stimulating factors (CSFs) regulate angiogenesis through activation of endothelial cell proliferation and migration. Since MSC are recruited within hypoxic tumors where they signal paracrine-regulated angiogenesis, the aim of this study was to evaluate which CSF members are expressed and are inducible in activated MSC. Furthermore, we investigated the JAK/STAT signal transducing pathway that may impact on CSF transcription. MSC were activated with Concanavalin-A (ConA), a TLR-2/6 agonist as well as a membrane type-1 matrix metalloproteinase (MT1-MMP) inducer, and we found increased transcription of granulocyte macrophage-CSF (GM-CSF, CSF-2), granulocyte CSF (G-CSF, CSF-3), and MT1-MMP. Gene silencing of either STAT3 or MT1-MMP prevented ConA-induced phosphorylation of STAT3, and reversed ConA effects on CSF-2 and CSF-3. Treatment with the Janus Kinase (JAK)2 inhibitor AG490 antagonized the ConA induction of MT1-MMP and CSF-2, while the pan-JAK inhibitor Tofacitinib reversed ConA-induced CSF-2 and -3 gene expression. Silencing of JAK2 prevented the ConA-mediated increase of CSF-2, while silencing of JAK1, JAK3 and TYK2 prevented the increase in CSF-3. Given that combined TLR-activation and locally-produced CSF-2 and CSF-3 could regulate immunomodulation and neovascularization, pharmacological targeting of TLR-2/6-induced MT1-MMP/JAK/STAT3 signalling pathway may prevent MSC contribution to tumor development.
机译：人骨髓来源的间充质基质细胞（MSC）表达Toll样受体（TLR）并产生细胞因子和趋化因子，所有这些都有助于这些细胞的免疫调节和促血管生成特性。在分泌的细胞因子中，集落刺激因子（CSF）通过激活内皮细胞增殖和迁移来调节血管生成。由于MSC是在缺氧肿瘤中募集的，它们通过信号表达旁分泌调节的血管生成，因此本研究的目的是评估活化的MSC中哪些CSF成员可以表达和诱导。此外，我们调查了可能影响CSF转录的JAK / STAT信号转导途径。 MSC被Concanavalin-A（ConA），TLR-2 / 6激动剂以及膜1型基质金属蛋白酶（MT1-MMP）诱导剂激活，我们发现粒细胞巨噬细胞CSF（GM-CSF， CSF-2），粒细胞CSF（G-CSF，CSF-3）和MT1-MMP。 STAT3或MT1-MMP的基因沉默可阻止ConA诱导的STAT3磷酸化，并逆转ConA对CSF-2和CSF-3的作用。用Janus Kinase（JAK）2抑制剂AG490的治疗拮抗了Con1-MTP和CSF-2的ConA诱导，而pan-JAK抑制剂Tofacitinib逆转了ConA诱导的CSF-2和-3基因表达。 JAK2沉默阻止了ConA介导的CSF-2的增加，而JAK1，JAK3和TYK2沉默阻止了CSF-3的增加。考虑到结合TLR激活和本地生产的CSF-2和CSF-3可以调节免疫调节和新血管形成，TLR-2 / 6诱导的MT1-MMP / JAK / STAT3信号通路的药理靶向可能会阻止MSC对肿瘤发展的贡献。

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