Heparin-binding epidermal growth factor-like growth factor inhibits cytokine-induced NF-κB activation and nitric oxide production via activation of the phosphatidylinositol 3-kinase pathway
Heparin-binding epidermal growth factor-like growth factor inhibits cytokine-induced NF-κB activation and nitric oxide production via activation of the phosphatidylinositol 3-kinase pathway
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DOI：
10.4049/jimmunol.175.3.1911
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发表时间：
2005-08-01
影响因子：
4.4
通讯作者：
Besner, GE
中科院分区：
文献类型：
--
作者：
Mehta, VB;Besner, GE
由诱导型NO合酶（iNOS）产生的NO参与包括炎症在内的多种病理生理过程。因此，NO合成或iNOS基因表达的抑制剂被认为是潜在的抗炎剂。我们以前已经证明，肝素结合表皮生长因子（EGF）样生长因子（HB-EGF）通过干扰NF-κ B信号通路，降低了在马槟榔刺激的肠上皮细胞中促炎细胞因子IL-8和NO的产生。然而，这些反应中涉及的上游信号机制尚未被定义。在这份报告中，我们表明，在肠上皮细胞，HB-EGF触发PI 3 K依赖的Akt磷酸化。抑制PI 3 K逆转了HB-EGF阻断NF-κ B活化、iNOS表达和NO产生的能力。PI 3 K的小干扰RNA也逆转了HB-EGF对iNOS表达的抑制作用。或者，组成型活性PI 3 K的瞬时表达使NO的产生比单独用HB-EGF治疗降低了2倍。这种PI 3 K效应是HB-EGF依赖性的。因此，PI 3 K的激活是必要的，但不足以减少NO的合成。PI 3 K和HB-EGF协同作用以减少NO合成。MEK、Ras或AM的过表达或抑制均不影响HB-EGF介导的NF-κ B活化抑制。这些数据表明，HB-EGF通过激活PI 3 K信号通路降低促炎性酪氨酸刺激的NF-κ B活化和NO产生。这些结果还表明，抑制NF-κ B和激活的PI 3 K依赖性信号级联反应的HB-EGF可能代表的关键信号负责的抗炎症作用HB-EGF。
NO produced by inducible NO synthase (iNOS) has been implicated in various pathophysiological processes including inflammation. Therefore, inhibitors of NO synthesis or iNOS gene expression have been considered as potential anti-inflammatory agents. We have previously demonstrated that heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) decreases proinflammatory cytokine IL-8 and NO production in cytokine-stimulated intestinal epithelial cells by interfering with the NF-kappa B signaling pathway. However, the upstream signaling mechanisms involved in these responses have not yet been defined. In this report, we show that in intestinal epithelial cells, HB-EGF triggered PI3K-dependent phosphorylation of Akt. Inhibition of PI3K reversed the ability of HB-EGF to block NF-kappa B activation, expression of iNOS, and NO production. Small interfering RNA of PI3K also reversed the inhibitory effect of HB-EGF on iNOS expression. Alternatively, transient expression of constitutively active PI3K decreased NO production by similar to 2-fold more than treatment with HB-EGF alone. This PI3K effect was HB-EGF dependent. Thus, activation of PI3K is essential but not sufficient for decreased NO synthesis. PI3K and HB-EGF act synergistically to decrease NO synthesis. Neither overexpression or inhibition of MEK, Ras, or AM affected HB-EGF-mediated inhibition of NF-kappa B activation. These data demonstrate that HB-EGF decreases proinflammatory cytokine-stimulated,NF-kappa B activation and NO production via activation of the PI3K signaling pathway. These results also suggest that inhibition of NF-kappa B and activation of the PI3K-dependent signaling cascade by HB-EGF may represent key signals responsible for the anti-inflammatory effects of HB-EGF.