Department of Vascular Biology, Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München, Ludwig-Maximilians-University of Munich (LMU), Feodor-Lynen-Straße 17, D-81377 Munich, Germany.
Institute of Biochemistry and Molecular Immunology, Medical Faculty, RWTH Aachen University, Pauwelsstrasse 30, D-52074 Aachen, Germany.
Cell Signal. 2018 Jun;46:32-42. doi: 10.1016/j.cellsig.2018.02.010. Epub 2018 Feb 21.
Macrophage migration inhibitory factor (MIF) is a chemokine-like inflammatory cytokine, which plays a pivotal role in the pathogenesis of inflammatory and cardiovascular diseases as well as cancer. We previously identified MIF as a novel B cell chemokine that promotes B cell migration through non-cognate interaction with the CXC chemokine receptor CXCR4 and CD74, the surface form of MHC class II invariant chain. In this study, we have analyzed the regulation of the MIF receptors under inflammatory conditions by investigating the impact of lipopolysaccharide (LPS), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) on CD74 and CXCR4 expression in B lymphocytes. We found that both LPS and TNF-α stimulation of primary B cells and the human B myeloma cell line RPMI-8226 enhanced protein expression as well as mRNA levels of CD74 in a time- and dose-dependent manner. By contrast, no effect on CXCR4 expression was observed. Selective inhibition of IκBα phosphorylation significantly attenuated LPS-induced expression of CD74, suggesting the contribution of NF-κB signaling pathways to the regulation of CD74 expression. Importantly, individual or simultaneous blockade of MIF or CD74 using specific neutralizing antibodies markedly affected B cell proliferation after LPS exposure. Taken together, our findings unveil a connection between the pro-proliferative activity of MIF/CD74 signaling in B cells and inflammation, offering novel target mechanisms in inflammatory cardiovascular or autoimmune pathogenesis.
巨噬细胞移动抑制因子（MIF）是一种趋化因子样炎症细胞因子，在炎症和心血管疾病以及癌症的发病机制中起着关键作用。我们之前发现 MIF 是一种新型 B 细胞趋化因子，通过与 CXC 趋化因子受体 CXCR4 和 MHC 类 II 不变链的表面形式 CD74 的非同源相互作用，促进 B 细胞迁移。在这项研究中，我们通过研究脂多糖（LPS）、肿瘤坏死因子-α（TNF-α）和白细胞介素-1β（IL-1β）对 B 淋巴细胞中 CD74 和 CXCR4 表达的影响，分析了炎症条件下 MIF 受体的调节。我们发现 LPS 和 TNF-α刺激原代 B 细胞和人 B 骨髓瘤细胞系 RPMI-8226 以时间和剂量依赖的方式增强 CD74 的蛋白表达和 mRNA 水平。相比之下，CXCR4 的表达没有受到影响。选择性抑制 IκBα 磷酸化显著减弱了 LPS 诱导的 CD74 表达，表明 NF-κB 信号通路对 CD74 表达的调节作用。重要的是，使用特异性中和抗体单独或同时阻断 MIF 或 CD74 明显影响 LPS 暴露后 B 细胞的增殖。总之，我们的研究结果揭示了 MIF/CD74 信号在 B 细胞中的促增殖活性与炎症之间的联系，为炎症性心血管或自身免疫发病机制中的新靶点机制提供了依据。
