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首页> 外文OA文献 >Blocking interferon γ reduces expression of chemokines CXCL9, CXCL10 and CXCL11 and decreases macrophage infiltration in ex vivo cultured arteries from patients with giant cell arteritis
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Blocking interferon γ reduces expression of chemokines CXCL9, CXCL10 and CXCL11 and decreases macrophage infiltration in ex vivo cultured arteries from patients with giant cell arteritis

机译：阻断干扰素γ可降低巨细胞性动脉炎患者离体培养动脉中趋化因子CXCL9，CXCL10和CXCL11的表达并减少巨噬细胞浸润

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BACKGROUND: Interferon γ (IFNγ) is considered a seminal cytokine in the pathogenesis of giant cell arteritis (GCA), but its functional role has not been investigated. We explored changes in infiltrating cells and biomarkers elicited by blocking IFNγ with a neutralising monoclonal antibody, A6, in temporal arteries from patients with GCA. METHODS: Temporal arteries from 34 patients with GCA (positive histology) and 21 controls were cultured on 3D matrix (Matrigel) and exposed to A6 or recombinant IFNγ. Changes in gene/protein expression were measured by qRT-PCR/western blot or immunoassay. Changes in infiltrating cells were assessed by immunohistochemistry/immunofluorescence. Chemotaxis/adhesion assays were performed with temporal artery-derived vascular smooth muscle cells (VSMCs) and peripheral blood mononuclear cells (PBMCs). RESULTS: Blocking endogenous IFNγ with A6 abrogated STAT-1 phosphorylation in cultured GCA arteries. Furthermore, selective reduction in CXCL9, CXCL10 and CXCL11 chemokine expression was observed along with reduction in infiltrating CD68 macrophages. Adding IFNγ elicited consistent opposite effects. IFNγ induced CXCL9, CXCL10, CXCL11, CCL2 and intracellular adhesion molecule-1 expression by cultured VSMC, resulting in increased PBMC chemotaxis/adhesion. Spontaneous expression of chemokines was higher in VSMC isolated from GCA-involved arteries than in those obtained from controls. Incubation of IFNγ-treated control arteries with PBMC resulted in adhesion/infiltration by CD68 macrophages, which did not occur in untreated arteries. CONCLUSIONS: Our ex vivo system suggests that IFNγ may play an important role in the recruitment of macrophages in GCA by inducing production of specific chemokines and adhesion molecules. Vascular wall components (ie, VSMC) are mediators of these functions and may facilitate progression of inflammatory infiltrates through the vessel wall.
机译：背景：干扰素γ（IFNγ）被认为是巨细胞性动脉炎（GCA）发病机理中的精浆细胞因子，但尚未研究其功能作用。我们探索了中和性单克隆抗体A6阻断GCA患者颞动脉中IFNγ引起的浸润细胞和生物标志物的变化。方法：将来自34名GCA（阳性组织学）患者和21名对照的颞动脉在3D基质（Matrigel）上培养，并暴露于A6或重组IFNγ。基因/蛋白质表达的变化通过qRT-PCR / western印迹或免疫测定来测量。通过免疫组织化学/免疫荧光评估浸润细胞的变化。用颞动脉衍生的血管平滑肌细胞（VSMC）和外周血单核细胞（PBMC）进行趋化性/粘附测定。结果：在培养的GCA动脉中，A6阻断内源性IFNγ消除了STAT-1的磷酸化。此外，观察到CXCL9，CXCL10和CXCL11趋化因子表达的选择性降低以及CD68巨噬细胞浸润的降低。添加IFNγ引起一致的相反作用。 IFNγ通过培养的VSMC诱导CXCL9，CXCL10，CXCL11，CCL2和细胞内粘附分子1表达，导致PBMC趋化性/粘附性增加。从涉及GCA的动脉中分离出的VSMC中趋化因子的自发表达高于从对照中获得的趋化因子。用PBMC孵育IFNγ处理的对照动脉会导致CD68巨噬细胞粘附/浸润，这在未经处理的动脉中不会发生。结论：我们的体外系统提示IFNγ可通过诱导特定趋化因子和粘附分子的产生在GCA募集巨噬细胞中发挥重要作用。血管壁成分（即，VSMC）是这些功能的介质，并且可以促进炎性浸润通过血管壁的进展。

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