Selective JAK/STAT3 signalling regulates transcription of colony stimulating factor-2 and -3 in Concanavalin-A-activated mesenchymal stromal cells.
Selective JAK/STAT3 signalling regulates transcription of colony stimulating factor-2 and -3 in Concanavalin-A-activated mesenchymal stromal cells.
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DOI：
10.1016/j.cyto.2013.04.027
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发表时间：
2013-05
期刊：
影响因子：
3.8
通讯作者：
Alain Zgheib;Émilie Pelletier-Bonnier;Louis-Charles Levros;B. Annabi
中科院分区：
文献类型：
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作者：
Alain Zgheib;Émilie Pelletier-Bonnier;Louis-Charles Levros;B. Annabi
人骨髓间充质干细胞（MSCs）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在缺氧肿瘤中被招募，在那里它们发出旁分泌调节血管生成的信号，因此本研究的目的是评估哪些CSF成员在活化的MSC中表达和诱导。此外，我们还研究了JAK/STAT信号转导通路可能对CSF转录的影响。用伴刀豆球蛋白A（ConA）、TLR-2/6激动剂以及膜1型基质金属蛋白酶（MT 1-MMP）诱导剂激活MSC，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MT 1-MMP的转录增加。STAT 3或MT 1-MMP的基因沉默阻止ConA诱导的STAT 3磷酸化，并逆转ConA对CSF-2和CSF-3的作用。用Janus激酶（JAK）2抑制剂AG 490处理拮抗ConA诱导的MT 1-MMP和CSF-2，而pan-JAK抑制剂托法替尼逆转ConA诱导的CSF-2和-3基因表达。JAK 2的沉默阻止了ConA介导的CSF-2的增加，而JAK 1、JAK 3和TYK 2的沉默阻止了CSF-3的增加。考虑到TLR激活和局部产生的CSF-2和CSF-3的组合可以调节免疫调节和新血管形成，TLR-2/6诱导的MT 1-MMP/JAK/STAT 3信号通路的药理学靶向可以防止MSC对肿瘤发展的贡献。
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.