Interferon gamma induces prostaglandin G/H synthase-2 through an autocrine loop via the epidermal growth factor receptor in human bronchial epithelial cells
Interferon gamma induces prostaglandin G/H synthase-2 through an autocrine loop via the epidermal growth factor receptor in human bronchial epithelial cells
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DOI：
10.1172/jci119233
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发表时间：
1997-03-01
影响因子：
15.9
通讯作者：
Drazen, JM
中科院分区：
文献类型：
--
作者：
Asano, K;Nakamura, H;Drazen, JM
前列腺素G/H合成酶的诱导（PGHS;在正常人支气管上皮细胞（NHBECs）的二次培养中，干扰素-γ（IFN-γ）通过促炎性细胞因子介导的前列腺素内过氧化物合酶（COX）至少部分地解释了炎性疾病中类花生酸生物合成的改变。（IFN-γ，10 ng/ml，24 h）增加了响应于外源性花生四烯酸（5 μ M）刺激而释放的前列腺素E（2）（PGE（2））的量。NHBECs中PGHS-2 RNA表达增加和PGHS-2蛋白回收增加表明PGHS-2表达上调，而IFN-γ对A549细胞中PGE（2）的产生无影响（人肺腺癌细胞系）或人脐静脉内皮细胞（HUVEC）中的6-酮-PGF（1 α），尽管前列腺素释放和/或PGHS-2 RNA在这些细胞系中的表达被其它促炎细胞因子上调。在IFN-γ处理的NHBECs中PGHS-2 RNA的诱导在24 h达到峰值，表明存在调节PGHS-2表达的中间物质。当表皮生长因子（EGF）受体与其配体之间的结合被中和抗体（LA-1）破坏时，IFN-γ不能上调NHBEC中PGE（2）的释放和PGHS-2 RNA的表达。此外，IFN-γ诱导EGF受体TGF-α上的许多配体的RNA表达;肝素结合EGF样生长因子（HB-EGF）;和双调蛋白，当外源性给药时，这些配体增加了NHBECs的PGE（2）释放，肝素的浓度中和了双调蛋白的功能，或抗TGF α或HB-EGF的抗体也减少了IFN-γ刺激的NHBEC释放PGE（2）。这些数据与支气管上皮细胞中存在调节PGHS-2表达和PGE（2）合成的自分泌生长因子/EGF受体环一致。
The induction of prostaglandin G/H synthase (PGHS; prostaglandin endoperoxide synthase, cyclooxygenase) by proinflammatory cytokines accounts, at least in part, for the altered eicosanoid biosynthesis in inflammatory diseases, In secondary cultures of normal human bronchial epithelial cells (NHBECs), interferon-gamma (IFN-gamma, 10 ng/ml for 24 h) increased the amount of prostaglandin E(2) (PGE(2)) released in response to stimulation with exogenous arachidonic acid (5 mu M). The enhanced production of PGE(2) reflected the upregulation of PGHS-2 as indicated by enhanced expression of PGHS-2 RNA and increased recovery of PGHS-2 protein in NHBECs, IFN-gamma did not alter the production of PGE(2) in A549 cells (a human lung adenocarcinoma cell line) or 6-keto-PGF(1 alpha) in human umbilical vein endothelial cells (HUVECs), although prostaglandin release and/or the expression of PGHS-2 RNA in these cell lines was upregulated by other proinflammatory cytokines. Induction of PGHS-2 RNA in IFN-gamma-treated NHBECs, which peaked at 24 h, suggested the presence of an intermediary substance regulating the expression of PGHS-2. When the binding between the epidermal growth factor (EGF) receptor and its ligands was disrupted by a neutralizing antibody (LA-1), IFN-gamma failed to upregulate the release of PGE(2) and the expression of PGHS-2 RNA in NHBECs. Furthermore, IFN-gamma induced the expression of RNAs for a number of ligands at the EGF receptor TGF-alpha; heparin-binding EGF-like growth factor (HB-EGF); and amphiregulin in NHBECs, and when administered exogenously, these ligands increased PGE(2) release from NHBECs, Heparin at the concentration that neutralized the function of amphiregulin, or antibodies against TGF alpha or HB-EGF also reduced the release of PGE(2) from IFN-gamma-stimulated NHBECs, These data are consistent with the presence of an autocrine growth factor/EGF receptor loop regulating PGHS-2 expression and PGE(2) synthesis in bronchial epithelial cells.