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首页> 外文期刊>Biochemical Pharmacology >H-RN, a novel antiangiogenic peptide derived from hepatocyte growth factor inhibits inflammation in vitro and in vivo through PI3K/AKT/IKK/NF-κB signal pathway
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H-RN, a novel antiangiogenic peptide derived from hepatocyte growth factor inhibits inflammation in vitro and in vivo through PI3K/AKT/IKK/NF-κB signal pathway

机译：H-RN是一种源自肝细胞生长因子的新型抗血管生成肽，可通过PI3K / AKT / IKK /NF-κB信号途径在体内和体外抑制炎症

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摘要

H-RN, a novel antiangiogenic peptide derived from the kringle 1 domain of hepatocyte growth factor (HGF), consists of the sequence RNPRGEEGGPW (molecular weight: 1254.34 Da). Emerging evidence indicates that HGF and the kringle domain exhibit anti-inflammatory effects in inflammatory diseases. In the present study, we assessed the anti-inflammatory effect of H-RN in models of experimental ocular inflammation, including endotoxin-induced uveitis (EIU) and experimental autoimmune uveitis (EAU). The results demonstrated that intravitreal treatment of H-RN concentration-dependently suppressed clinical manifestation, inhibited ocular inflammatory cytokine production and improved histopathologic scores. Moreover, H-RN attenuated the LPS-induced mRNA and protein expression of tumor necrosis factor (TNF)-α and interleukin (IL)-6 in RAW 264.7 cells and inhibited cell chemotactic migration toward LPS. We also demonstrated that H-RN suppressed TNF-α-induced adhesion molecule expression in HUVECs, including ICAM-1, VCAM-1 and E-selectin, which contributed to its suppressive effect on adherence of U937 cells to endothelial cells. We also demonstrated the possible anti-inflammation mechanism of H-RN. Western blot and immunofluorescence staining analyses revealed that H-RN significantly suppressed LPS-induced phosphorylation of nuclear factor (NF)-κB-p65 at Ser276. Based on examination of upstream pathways, we found that H-RN inhibited PI3K-p85 and AKTSer473 phosphorylation, which may result in the attenuation of LPS-induced IKK complex activation and IκB degradation. Thus, our studies suggest that the 11-amino-acid peptide H-RN exhibits anti-inflammatory effects in vitro and in vivo and may represent a promising candidate for ocular inflammatory diseases.
机译：H-RN是一种衍生自肝细胞生长因子（HGF）kringle 1结构域的新型抗血管生成肽，由序列RNPRGEEGGPW（分子量：1254.34 Da）组成。新兴证据表明，HGF和kringle域在炎性疾病中表现出抗炎作用。在本研究中，我们评估了H-RN在实验性眼部炎症模型（包括内毒素诱发的葡萄膜炎（EIU）和实验性自身免疫性葡萄膜炎（EAU））中的抗炎作用。结果表明玻璃体内治疗H-RN浓度依赖性地抑制了临床表现，抑制了眼部炎症细胞因子的产生并改善了组织病理学评分。此外，H-RN减弱了RAW 264.7细胞中LPS诱导的肿瘤坏死因子（TNF）-α和白介素（IL）-6的mRNA和蛋白表达，并抑制了细胞向LPS趋化迁移。我们还证明了H-RN抑制HUVEC中TNF-α诱导的粘附分子表达，包括ICAM-1，VCAM-1和E-选择素，这有助于其抑制U937细胞与内皮细胞的粘附。我们还证明了H-RN可能的抗炎机制。 Western印迹和免疫荧光染色分析表明，H-RN显着抑制LPS诱导的Ser276核因子（NF）-κB-p65磷酸化。在检查上游途径的基础上，我们发现H-RN抑制了PI3K-p85和AKTSer473磷酸化，这可能导致LPS诱导的IKK复合物激活和IκB降解的减弱。因此，我们的研究表明，11个氨基酸的肽H-RN在体外和体内均具有抗炎作用，并且可能代表了眼部炎性疾病的有希望的候选者。

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