Unité de Glycobiologie Structurale et Fonctionnelle, Unité Mixte de Recherche 8576 du Centre National de la Recherche Scientifique, Institut Fédératif de Recherche 147, Université Lille Nord de France-Université des Sciences et Technologies, Villeneuve d'Ascq 59655, France.
J Immunol. 2012 Aug 15;189(4):2023-32. doi: 10.4049/jimmunol.1102803. Epub 2012 Jul 13.
Extracellular cyclophilin A (CyPA) and CyPB have been well described as chemotactic factors for various leukocyte subsets, suggesting their contribution to inflammatory responses. Unlike CyPA, CyPB accumulates in extracellular matrixes, from which it is released by inflammatory proteases. Hence, we hypothesized that it could participate in tissue inflammation by regulating the activity of macrophages. In the current study, we confirmed that CyPB initiated in vitro migration of macrophages, but it did not induce production of proinflammatory cytokines. In contrast, pretreatment of macrophages with CyPB attenuated the expression of inflammatory mediators induced by LPS stimulation. The expression of TNF-α mRNA was strongly reduced after exposure to CyPB, but it was not accompanied by significant modification in LPS-induced activation of MAPK and NF-κB pathways. LPS activation of a reporter gene under the control of TNF-α gene promoter was also markedly decreased in cells treated with CyPB, suggesting a transcriptional mechanism of inhibition. Consistent with this hypothesis, we found that CyPB induced the expression of B cell lymphoma-3 (Bcl-3), which was accompanied by a decrease in the binding of NF-κB p65 to the TNF-α promoter. As expected, interfering with the expression of Bcl-3 restored cell responsiveness to LPS, thus confirming that CyPB acted by inhibiting initiation of TNF-α gene transcription. Finally, we found that CyPA was not efficient in attenuating the production of TNF-α from LPS-stimulated macrophages, which seemed to be due to a modest induction of Bcl-3 expression. Collectively, these findings suggest an unexpected role for CyPB in attenuation of the responses of proinflammatory macrophages.
细胞外亲环素 A（CyPA）和 CyPB 已被充分描述为各种白细胞亚群的趋化因子，表明它们参与炎症反应。与 CyPA 不同，CyPB 聚集在细胞外基质中，由炎症蛋白酶释放。因此，我们假设它可以通过调节巨噬细胞的活性来参与组织炎症。在本研究中，我们证实 CyPB 可启动体外巨噬细胞迁移，但不会诱导促炎细胞因子的产生。相比之下，CyPB 预处理可减轻 LPS 刺激诱导的炎症介质的表达。暴露于 CyPB 后，TNF-αmRNA 的表达强烈减少，但 LPS 诱导的 MAPK 和 NF-κB 途径的激活没有显著改变。在 CyPB 处理的细胞中，受 TNF-α基因启动子控制的报告基因的 LPS 激活也明显降低，表明存在转录抑制机制。与该假说一致，我们发现 CyPB 诱导 B 细胞淋巴瘤-3（Bcl-3）的表达，同时 NF-κB p65 与 TNF-α启动子的结合减少。正如预期的那样，干扰 Bcl-3 的表达恢复了细胞对 LPS 的反应性，从而证实 CyPB 通过抑制 TNF-α基因转录的起始来发挥作用。最后，我们发现 CyPA 不能有效减弱 LPS 刺激的巨噬细胞中 TNF-α的产生，这似乎是由于 Bcl-3 表达的适度诱导。总之，这些发现表明 CyPB 在减弱促炎巨噬细胞反应中具有意想不到的作用。
