Fritz Dominik K, Kerr Christine, Tong Li, Smyth David, Richards Carl D
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
J Immunol. 2006 Apr 1;176(7):4352-60. doi: 10.4049/jimmunol.176.7.4352.
Oncostatin-M (OSM) is an IL-6/gp130 family member that can stimulate the eosinophil-selective CC chemokine eotaxin-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(-/-) MLF. 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 MLF. 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.
抑瘤素-M（OSM）是白细胞介素-6/糖蛋白130家族成员，它在体外可刺激嗜酸性粒细胞选择性CC趋化因子嗜酸性粒细胞趋化因子-1，并在体内促使嗜酸性粒细胞在小鼠肺中积聚。在哮喘动物模型中，黏附分子血管细胞黏附分子-1（VCAM-1）和嗜酸性粒细胞趋化因子与嗜酸性粒细胞外渗并积聚到组织中有关。在本研究中，我们调查了OSM在调节VCAM-1表达以及小鼠成纤维细胞中信号转导和转录激活因子6（STAT6）酪氨酸641磷酸化方面的作用。体外实验中，OSM在蛋白质和mRNA水平上诱导C57BL/6小鼠肺成纤维细胞（MLF）和NIH 3T3成纤维细胞中VCAM-1的表达。OSM还诱导MLF和NIH 3T3成纤维细胞中STAT6 Y641磷酸化，其他白细胞介素-6/糖蛋白130细胞因子家族成员（白细胞介素-6、白血病抑制因子、心肌营养素-1和白细胞介素-11）以及来自信号转导和转录激活因子6基因敲除（STAT6(-/-)）小鼠的细胞（STAT6(-/-) MLF）中均未观察到这种活性。在STAT6(-/-) MLF中评估发现，STAT6对于OSM诱导的VCAM-1或嗜酸性粒细胞趋化因子-1并非必需。白细胞介素-4（IL-4）和OSM联合使用可协同增强MLF中嗜酸性粒细胞趋化因子-1的表达。然而，在STAT6(-/-) MLF中，IL-4诱导以及IL-4/OSM对嗜酸性粒细胞趋化因子-1的协同诱导作用均被消除，而白细胞介素-6在STAT6基因敲除或野生型MLF中的调节作用相似。OSM诱导的VCAM-1表达可被磷脂酰肌醇-3激酶（PI3K）的药理抑制剂（LY294002）减弱，但不能被细胞外信号调节激酶1/2（ERK1/2）抑制剂（PD98059）或p38丝裂原活化蛋白激酶（p38 MAPK）抑制剂（SB203580）减弱。这些数据支持了OSM通过嗜酸性粒细胞趋化因子-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能够通过其受体复合物OSM受体β链和糖蛋白130诱导独特信号转导事件的观点。
