Activation of NF-κB by the human herpesvirus 8 chemokine receptor ORF74:: Evidence for a paracrine model of Kaposi's sarcoma pathogenesis
Activation of NF-κB by the human herpesvirus 8 chemokine receptor ORF74:: Evidence for a paracrine model of Kaposi's sarcoma pathogenesis
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DOI：
10.1128/jvi.75.18.8660-8673.2001
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发表时间：
2001-09-01
影响因子：
5.4
通讯作者：
Reitz, M
中科院分区：
文献类型：
--
作者：
Pati, S;Cavrois, M;Reitz, M
感染人类疱疹病毒8 (HHV-8)，也被称为卡波西肉瘤（KS）相关疱疹病毒，是KS发展的必要条件。HHV-8裂解期基因ORF74与G蛋白偶联受体，特别是白细胞介素-8 （IL-8）受体有关。ORF74激活肌醇磷酸/磷脂酶C途径和下游的丝裂原活化蛋白激酶JNK/SAPK和p38。我们在这里表明，ORF74在ks来源的hhv -8阴性内皮细胞或原代血管内皮细胞中表达时，也能独立于配体激活NF-KB。趋化因子GRO α可增强NF-KB的激活，而IL-8则不能。ORF74第二细胞质环Val向Asp的突变不影响配体非依赖性信号活性，但大大增加了对GRO α的响应。ORF74上调nf - kappab依赖性炎症细胞因子（RANTES、IL-6、IL-8和粒细胞-巨噬细胞集落刺激因子）和粘附分子（VCAM-1、ICAM-1和e-选择素）的表达。转染的KS细胞的上清液激活了未转染细胞中的NF-KB信号，并引发了单核细胞和t淋巴细胞的趋化性。ORF74的表达使原代内皮细胞的形态与KS病变中梭形细胞的形态惊人地相似。综上所述，这些数据表明ORF74激活NF-KB并诱导促血管生成因子和促炎症因子的表达，这表明ORF74在少数KS病变细胞中的表达可能通过自分泌和旁分泌机制影响未感染细胞或潜伏感染细胞，从而参与KS的发病机制。
Infection with human herpesvirus 8 (HHV-8), also known as Kaposi's sarcoma (KS)-associated herpesvirus, is necessary for the development of KS. The HHV-8 lytic-phase gene ORF74 is related to G protein-coupled receptors, particularly interleukin-8 (IL-8) receptors. ORF74 activates the inositol phosphate/phospholipase C pathway and the downstream mitogen-activated protein kinases, JNK/SAPK and p38. We show here that ORF74 also activates NF-KB independent of ligand when expressed in KS-derived HHV-8-negative endothelial cells or primary vascular endothelial cells. NF-KB activation was enhanced by the chemokine GRO alpha, but not by IL-8. Mutation of Val to Asp in the ORF74 second cytoplasmic loop did not affect ligand-independent signaling activity, but it greatly increased the response to GRO alpha. ORF74 upregulated the expression of NF-kappaB-dependent inflammatory cytokines (RANTES, IL-6, IL-8, and granulocyte-macrophage colony-stimulating factor) and adhesion molecules (VCAM-1, ICAM-1, and E-selectin). Supernatants from transfected KS cells activated NF-KB signaling in untransfected cells and elicited the chemotaxis of monocytoid and T-lymphoid cells. Expression of ORF74 conferred on primary endothelial cells a morphology that was strikingly similar to that of spindle cells present in KS lesions. Taken together, these data, demonstrating that ORF74 activates NF-KB and induces the expression of proangiogenic and proinflammatory factors, suggest that expression of ORF74 in a minority of cells in KS lesions could influence uninfected cells or latently infected cells via autocrine and paracrine mechanisms, thereby contributing to KS pathogenesis.