Camozzi Maura, Rusnati Marco, Bugatti Antonella, Bottazzi Barbara, Mantovani Alberto, Bastone Antonio, Inforzato Antonio, Vincenti Silvia, Bracci Luisa, Mastroianni Domenico, Presta Marco
Unit of General Pathology and Immunology, Department of Biomedical Sciences and Biotechnology, School of Medicine, University of Brescia, 25123 Brescia, Italy.
J Biol Chem. 2006 Aug 11;281(32):22605-13. doi: 10.1074/jbc.M601023200. Epub 2006 Jun 12.
Long-pentraxin 3 (PTX3) is a soluble pattern recognition receptor with non-redundant functions in inflammation and innate immunity. PTX3 comprises a pentraxin-like C-terminal domain involved in complement activation via C1q interaction and an N-terminal extension with unknown functions. PTX3 binds fibroblast growth factor-2 (FGF2), inhibiting its pro-angiogenic and pro-restenotic activity. Here, retroviral transduced endothelial cells (ECs) overexpressing the N-terminal fragment PTX3-(1-178) showed reduced mitogenic activity in response to FGF2. Accordingly, purified recombinant PTX3-(1-178) binds FGF2, prevents PTX3/FGF2 interaction, and inhibits FGF2 mitogenic activity in ECs. Also, the monoclonal antibody mAb-MNB4, which recognizes the PTX3-(87-99) epitope, prevents FGF2/PTX3 interaction and abolishes the FGF2 antagonist activity of PTX3. Consistently, the synthetic peptides PTX3-(82-110) and PTX3-(97-110) bind FGF2 and inhibit the interaction of FGF2 with PTX3 immobilized to a BIAcore sensor chip, FGF2-dependent EC proliferation, and angiogenesis in vivo. Thus, the data identify a FGF2-binding domain in the N-terminal extension of PTX3 spanning the PTX3-(97-110) region, pointing to a novel function for the N-terminal extension of PTX3 and underlining the complexity of the PTX3 molecule for modular humoral pattern recognition.
长五聚体蛋白3（PTX3）是一种可溶性模式识别受体，在炎症和天然免疫中具有独特功能。PTX3包含一个通过与C1q相互作用参与补体激活的五聚体样C末端结构域和一个功能未知的N末端延伸区。PTX3与成纤维细胞生长因子-2（FGF2）结合，抑制其促血管生成和促再狭窄活性。在此，过表达N末端片段PTX3-(1-178)的逆转录病毒转导内皮细胞（ECs）对FGF2的促有丝分裂活性降低。相应地，纯化的重组PTX3-(1-178)与FGF2结合，阻止PTX3/FGF2相互作用，并抑制ECs中FGF2的促有丝分裂活性。此外，识别PTX3-(87-99)表位的单克隆抗体mAb-MNB4可阻止FGF2/PTX3相互作用，并消除PTX3的FGF2拮抗剂活性。一致地，合成肽PTX3-(82-110)和PTX3-(97-110)与FGF2结合，并抑制FGF2与固定在BIAcore传感器芯片上的PTX3的相互作用、FGF2依赖的EC增殖以及体内血管生成。因此，这些数据确定了PTX3 N末端延伸区中跨越PTX3-(97-110)区域的FGF2结合结构域，揭示了PTX3 N末端延伸区的新功能，并强调了PTX3分子在模块化体液模式识别中的复杂性。
