Blunted activation of NF-κB and NF-κB-dependent gene expression by geranylgeranylacetone:: Involvement of unfolded protein response
Blunted activation of NF-κB and NF-κB-dependent gene expression by geranylgeranylacetone:: Involvement of unfolded protein response
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DOI：
10.1016/j.bbrc.2007.10.115
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发表时间：
2008-01-04
影响因子：
3.1
通讯作者：
Kitamura, Masanori
中科院分区：
文献类型：
--
作者：
Hayakawa, Kunihiro;Hiramatsu, Nobuhiko;Kitamura, Masanori
香叶基香叶基丙酮（GGA）是一种抗溃疡剂，对实验性结肠炎和缺血诱导的肾脏炎症具有抗炎作用。然而，涉及其抗炎作用的分子机制在很大程度上是未知的。我们发现，在肾小球系膜细胞，GGA阻断核因子-κ B的激活和随后的诱导单核细胞趋化蛋白1（MCP-1）的炎症细胞因子。它与未折叠蛋白反应（UPR）的诱导呈负相关，证明了78 kDa的葡萄糖调节蛋白（GRP 78）的表达和内质网应激反应性碱性磷酸酶的抑制。UPR的诱导剂包括衣霉素、毒胡萝卜素、A23187、2-脱氧葡萄糖、二硫苏糖醇和AB（5）枯草杆菌酶细胞毒素都能复制GGA的抑制作用。此外，通过稳定转染GRP 78减弱UPR降低了GGA的抗炎作用。这些结果揭示了一种新的，UPR依赖的机制，潜在的抗炎潜力的GGA。(c)2007年爱思唯尔公司All rights reserved.
Geranylgeranylacetone (GGA), an anti-ulcer agent, has anti-inflammatory potential against experimental colitis and ischemia-induced renal inflammation. However, molecular mechanisms involved in its anti-inflammatory effects are largely unknown. We found that, in glomerular mesangial cells, GGA blocked activation of nuclear factor-kappa B and consequent induction of monocyte chemoattractant protein 1 (MCP-1) by inflammatory cytokines. It was inversely correlated with induction of unfolded protein response (UPR) evidenced by expression of 78 kDa glucose-regulated protein (GRP78) and suppression of endoplasmic reticulum stress-responsive alkaline phosphatase. Various inducers of UPR including tunicamycin, thapsigargin, A23187, 2-deoxyglucose, dithiothreitol, and AB(5) subtilase cytotoxin reproduced the suppressive effects of GGA. Furthermore, attenuation of UPR by stable transfection with GRP78 diminished the anti-inflammatory effects of GGA. These results disclosed a novel, UPR-dependent mechanism underlying the anti-inflammatory potential of GGA. (c) 2007 Elsevier Inc. All rights reserved.