S632A3, a new glutarimide antibiotic, suppresses lipopolysaccharide-induced pro-inflammatory responses via inhibiting the activation of glycogen synthase kinase 3β
S632A3, a new glutarimide antibiotic, suppresses lipopolysaccharide-induced pro-inflammatory responses via inhibiting the activation of glycogen synthase kinase 3β
复制标题
DOI：
10.1016/j.yexcr.2012.08.008
复制
发表时间：
2012-12-10
影响因子：
3.7
通讯作者：
Li, Diandong
中科院分区：
文献类型：
--
作者：
Deng, Hongbin;Zhang, Na;Li, Diandong
炎症介质包括诱导型一氧化氮合酶(INOS)、环氧合酶-2(COX-2)、肿瘤坏死因子-α(INF-α)和白介素6(IL-6)，参与了多种炎症性疾病的发病过程。S632A3是从吸水链霉菌S632发酵液中分离得到的具有较强的核因子-kappaB抑制活性的戊二酰亚胺类抗生素的新成员。本研究旨在探讨S632A3对内毒素刺激的RAW264.7巨噬细胞的抗炎作用及其分子机制。S632A3通过在基因转录水平抑制iNOS和COX-2，浓度依赖性地抑制内毒素诱导的NO和前列腺素E-2(PGE(2))的产生。此外，S632A3通过抑制糖原合成酶3β(GSK-3β)的激活而抑制依赖于NF-kappa B的炎症反应，而不影响I kappa B激酶(IKK)复合体的激活。S632A3通过不同程度地影响cAMP反应元件结合蛋白(CREB)和核因子-kappaB p65与辅活化子CBP(CREB结合蛋白)相互作用来抑制核因子-kappaB的活性。S632A3还可抑制GSK-3β诱导的iNOS和COX-2的表达。此外，S632A3还能抑制巨噬细胞中ASK1和p38丝裂原活化蛋白激酶的激活，从而减弱内毒素诱导的巨噬细胞内核因子-kappaB的活性。此外，S632A3还能显著降低内毒素刺激的RAW264.7细胞产生的促炎细胞因子TNF-α和IL-6，增加抗炎细胞因子IL-10的产生。因此，我们的研究提供了S632A3通过干扰GSK-3β和ASK1-p38信号的激活来抑制内毒素诱导的巨噬细胞促炎反应的分子机制。(C)2012 Elsevier Inc.保留所有权利。
Inflammatory mediators including inducible nitric oxide (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-alpha (INF-alpha) and Interleukin-6 (IL-6) contribute to the course of a variety of inflammatory diseases. S632A3 is a new member of the glutarimide antibiotics isolated from a cultured broth of Streptomyces hygroscopicus S632 with a potent NF-kappa B inhibitory activity. In the present study, we investigated the anti-inflammatory effects and the underlying molecular mechanism of S632A3 on lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. S632A3 concentration-dependently inhibited LPS-induced NO and prostaglandin E-2 (PGE(2)) production through the suppression of iNOS and COX-2 at gene transcription levels. In addition, S632A3 suppressed NF-kappa B-dependent inflammatory responses by inhibiting the activation of glycogen synthase kinase 3 beta (GSK-3 beta), while the activation of I kappa B kinase (IKK) complex was unaffected. S632A3 suppressed NF-kappa B activity by differentially affecting the CREB (cAMP response element-binding protein) and NF-kappa B p65 interacting with the coactivator CBP (CREB binding protein). S632A3 also inhibited GSK-3 beta-elicited iNOS and COX-2 expression. Moreover, S632A3 was shown to inhibit the activation of ASK1 (Apoptosis-signal regulating kinase 1) and p38 mitogen-activated protein kinase, therefore attenuated the LPS-induced NF-kappa B activity in macrophages. Furthermore, S632A3 significantly reduced the pro-inflammatory cytokines TNF-alpha and IL-6 production while increased the anti-inflammatory cytokine IL-10 production in LPS-stimulated RAW264.7 cells. Our study thus provides a molecular mechanism by which S632A3 inhibited LPS-induced pro-inflammatory response in macrophages through interfering with the activation of GSK-3 beta and ASK1-p38 signaling. (C) 2012 Elsevier Inc. All rights reserved.