MFG-E8-derived peptide attenuates adhesion and migration of immune cells to endothelial cells
MFG-E8-derived peptide attenuates adhesion and migration of immune cells to endothelial cells
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源自 MFG-E8 的肽可减少免疫细胞对内皮细胞的粘附和迁移
DOI：
10.1189/jlb.3a0416-184rr
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发表时间：
2017-05-01
影响因子：
5.5
通讯作者：
Wang, Ping
中科院分区：
文献类型：
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作者：
Hirano, Yohei;Yang, Weng-Lang;Wang, Ping
乳脂球-表皮生长因子-因子8 （MFG-E8）在炎症性疾病中起免疫调节作用。mfg - e8衍生短肽（MSP68）可显著减少脓毒症时肺中性粒细胞的浸润和损伤。本研究探讨了MSP68对多种免疫细胞趋化性的影响及其调控机制。采用Transwell法检测C57BL/6小鼠骨髓源性中性粒细胞（bmdn）、人单核细胞THP-1细胞系和人T淋巴细胞Jurkat细胞系在MSP68作用下的粘附和迁移。MSP68显著抑制tnf - α刺激的肺动脉内皮细胞（PAEC）单层上的BMDN和THP-1细胞粘附，但对Jurkat细胞粘附无剂量依赖性。MSP68也显著降低了BMDN在vcam -1包被孔上的粘附。表面等离子体共振（SPR）分析显示，MSP68在解离常数（KD）为1.53 × 10(-7) m时有效识别整合素α (4) β (1) （VCAM-1受体）。这些发现表明，MSP68通过干扰中性粒细胞上的整合素a4b1与内皮细胞上的VCAM-1的结合，阻止中性粒细胞粘附到活化的内皮细胞上。此外，MSP68显著减弱BMDN和THP-1细胞对其趋化剂的迁移，但不影响Jurkat细胞对其趋化剂的迁移。MSP68预处理抑制了bmdn在paec中向化学引诱剂、fMLP、MIP-2和补体片段5a （C5a）的迁移，并呈剂量依赖性。最后，我们发现fMLP对bmdn中p38 MAPK的激活被MSP68抑制。因此，MSP68减少了免疫细胞通过内皮细胞内膜向炎症组织的外渗，这意味着MSP68是一种新的治疗免疫细胞过度浸润引起的炎症性疾病的药物。
Milk fat globule-epidermal growth factor-factor 8 (MFG-E8) plays an immunomodulatory role in inflammatory diseases. MFG-E8-derived short peptide (MSP68) greatly reduces neutrophil infiltration and injury in the lung during sepsis. In this study, we examined the effect of MSP68 on chemotaxis of various immune cells and its regulatory mechanism. Bone marrow-derived neutrophils (BMDNs) from C57BL/6 mice, human monocyte THP-1 cell line, and human T lymphocyte Jurkat cell line were used for adhesion and migration assays using a Transwell method in the presence of MSP68. Treatment with MSP68 significantly inhibited the BMDN and THP-1 cell but not Jurkat cell adhesion on the TNF-alpha-stimulated pulmonary artery endothelial cell (PAEC) monolayer dose-dependently. MSP68 also significantly reduced BMDN adhesion on VCAM-1-coated wells dose dependently. Surface plasmon resonance (SPR) analysis revealed that MSP68 efficiently recognized integrin alpha(4)beta(1) (receptor for VCAM-1) at the dissociation constant (KD) of 1.53 x 10(-7) M. These findings implicate that MSP68 prevents neutrophil adhesion to the activated endothelial cells by interfering with the binding between integrin a4b1 on neutrophils and VCAM-1 on endothelial cells. Moreover, MSP68 significantly attenuated the migration of BMDN and THP-1 cells but not Jurkat cells to their chemoattractants. Pretreatment with MSP68 inhibited the transmigration of BMDNs across the PAECs toward chemoattractants, fMLP, MIP-2, and complement fragment 5a (C5a) dose-dependently. Finally, we identified that the activation of p38 MAPK in BMDNs by fMLP was inhibited by MSP68. Thus, MSP68 attenuates extravasation of immune cells through the endothelial cell lining into inflamed tissue, implicating MSP68 to be a novel, therapeutic agent for inflammatory diseases caused by excessive immune cell infiltration.