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
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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DOI：
10.1016/j.bcp.2014.02.026
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发表时间：
2014-05-15
影响因子：
5.8
通讯作者：
Xu, Xun
中科院分区：
文献类型：
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作者：
Wang, Lili;Xu, Yan;Xu, Xun
H-RN是肝细胞生长因子（HGF）kringle 1结构域衍生的一种新的抗血管生成肽，序列为RNPRGEEGGPW（分子量：1254.34 Da）。新出现的证据表明HGF和Kringle结构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中的抗炎作用，包括内毒素诱导的葡萄膜炎（EIU）和实验性自身免疫性葡萄膜炎（EAU）。结果表明，玻璃体内注射H-RN浓度依赖性地抑制临床表现，抑制眼部炎症细胞因子的产生，并改善组织病理学评分。此外，H-RN减弱LPS诱导的RAW 264.7细胞中肿瘤坏死因子（TNF）-α和白细胞介素（IL）-6的mRNA和蛋白表达，并抑制细胞向LPS的趋化迁移。我们还证明，H-RN抑制TNF-α诱导的粘附分子在HUVECs中的表达，包括ICAM-1，VCAM-1和E-选择素，这有助于其对U937细胞与内皮细胞粘附的抑制作用。并初步探讨了H-RN的抗炎作用机制。Western blot和免疫荧光染色分析显示，H-RN显着抑制LPS诱导的核因子（NF）-κ B-p65的Ser 276磷酸化。基于对上游通路的检测，我们发现H-RN抑制PI 3 K-p85和AKT（Ser 473）磷酸化，这可能导致LPS诱导的IKK复合物活化和I κ B降解的减弱。因此，我们的研究表明，11个氨基酸的肽H-RN在体外和体内表现出抗炎作用，并可能代表一个有前途的候选人的眼部炎症性疾病。(C)2014爱思唯尔公司All rights reserved.
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)-alpha and interleukin (IL)-6 in RAW 264.7 cells and inhibited cell chemotactic migration toward LPS. We also demonstrated that H-RN suppressed TNF-alpha-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)-kappa B-p65 at Ser276. Based on examination of upstream pathways, we found that H-RN inhibited PI3K-p85 and AKT(Ser473) phosphorylation, which may result in the attenuation of LPS-induced IKK complex activation and I kappa B 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. (C) 2014 Elsevier Inc. All rights reserved.