Oncostatin-M up-regulates VCAM-1 and synergizes with IL-4 in eotaxin expression: Involvement of STAT6
Oncostatin-M up-regulates VCAM-1 and synergizes with IL-4 in eotaxin expression: Involvement of STAT6
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DOI：
10.4049/jimmunol.176.7.4352
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发表时间：
2006-04-01
影响因子：
4.4
通讯作者：
Richards, Carl D.
中科院分区：
文献类型：
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作者：
Fritz, Dominik K.;Kerr, Christine;Richards, Carl D.
Oncostatin-M (OSM) 是 IL-6/gp130 家族成员，可在体外刺激嗜酸性粒细胞选择性 CC 趋化因子 cotaxin-1，在体内刺激小鼠肺部嗜酸性粒细胞积聚。在哮喘动物模型中，粘附分子 VCAM-1 和嗜酸性粒细胞趋化因子与嗜酸性粒细胞外渗和积聚到组织中有关。在本研究中，我们研究了 OSM 在调节小鼠成纤维细胞中 VCAM-1 表达和 STAT6 酪氨酸 641 磷酸化中的作用。 OSM 在体外诱导 C57BL/6 小鼠肺成纤维细胞 (MLF) 和 NIH 3T3 成纤维细胞中蛋白质和 mRNA 水平的 VCAM-1 表达。 OSM 还在 MLF 和 NIH 3T3 成纤维细胞中诱导 STAT6 Y641 磷酸化，这种活性在其他 IL-6/gp130 细胞因子家族成员（IL-6、白血病抑制因子、心肌素-1 和 IL-11）以及来自 STAT6(-/-) 小鼠的细胞 (STAT6-/- MLF) 中均未观察到。根据 STAT6(-/-) MILE 中的评估，STAT6 对于 OSM 诱导的 VCAM-1 或 eotaxin-1 不是必需的。IL-4 和 OSM 的组合可协同增强 MLF 中的 eotaxin-1 表达。 IL-4 诱导和 IL-4/OSM 对eotaxin-1 的协同诱导在 STAT6(-/-) MLF 中被消除，然而，IL-6 的调节在 -/- 或野生型 MILE 中相似 OSM 对 VCAM-1 的诱导被 PI3K (LY294002) 药理抑制剂减弱，但 ERK1/2 (PD98059) 或 p38 MAPK 抑制剂没有减弱(SB203580)。这些数据支持 OSM 通过 eotaxin-1 和 VCAM-1 表达在嗜酸性粒细胞积聚到肺组织中的作用，以及 OSM 能够通过其 OSMR β 链和 gp130 受体复合物诱导独特的信号转导事件的观点。
Oncostatin-M (OSM) is an IL-6/gp130 family member that can stimulate the eosinophil-selective CC chemokine cotaxin-1 in vitro and eosinophil accumulation in mouse lung in vivo. The adhesion molecule VCAM-1 and eotaxin have been implicated in extravasation and accumulation of eosinophils into tissue in animal models of asthma. In this study, we investigated the role of OSM in regulation of VCAM-1 expression, and STAT6 tyrosine 641 phosphorylation in murine fibroblasts. OSM induced VCAM-1 expression in C57BL/6 mouse lung fibroblasts (MLF) and NIH 3T3 fibroblasts at the protein and mRNA level in vitro. OSM also induced STAT6 Y641 phosphorylation in MLF and NIH 3T3 fibroblasts, an activity not observed with other IL-6/gp130 cytokine family members (IL-6, leukemia inhibitory factor, cardiotropin-1, and IL-11) nor in cells derived from STAT6(-/-) mice (STAT6-/- MLF). STAT6 was not essential for OSM-induced VCAM-1 or eotaxin-1 as assessed in STAT6(-/-) MILE Combination of IL-4 and OSM synergistically enhanced eotaxin-1 expression in MLF. IL-4 induction and the IL-4/OSM synergistic induction of eotaxin-1 was abrogated in STAT6(-/-) MLF, however, regulation of IL-6 was similar in -/- or wild-type MILE Induction of VCAM-1 by OSM was diminished by pharmacological inhibitors of PI3K (LY294002) but not inhibitors of ERK1/2 (PD98059) or p38 MAPK (SB203580). These data support the role of OSM in eosinophil accumulation into lung tissue through eotaxin-1 and VCAM-1 expression and the notion that OSM is able to induce unique signal transduction events through its receptor complex of OSMR beta-chain and gp130.