Xu Y X, Pindolia K R, Janakiraman N, Noth C J, Chapman R A, Gautam S C
Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan 48202, USA.
Exp Hematol. 1997 May;25(5):413-22.
Chemotactic cytokines or chemokines play an important role in the regulation of myelopoiesis. Since the production of chemokines and colony stimulating factors (CSFs) by bone marrow stromal cells requires inflammatory conditions, we investigated the effect of curcumin, an agent with anti-inflammatory and anti-oxidant activities, on the expression of monocyte chemoattractant protein-1 (MCP-1 or MCP-1/JE) and interferon inducible protein-10kD (IP-10) in mouse bone marrow stromal cell line +/+-1.LDA11. Both chemokines are readily expressed in stromal cells after stimulation with pro-inflammatory interleukin-1alpha (IL-1alpha), interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), and endotoxin lipopolysaccharide (LPS). Curcumin attenuates the levels of MCP-1/JE and IP-10 mRNA expression by all of these stimulatory agents. A detailed analysis of the regulatory effects of curcumin on chemokine expression by IL-1alpha was performed. Curcumin inhibits both chemokine mRNAs in a dose- and time-dependent manner. The suppressive effect of curcumin on both mRNAs is reversible with complete recovery from suppression within 24 hours after removal of curcumin. The suppression of mRNA by curcumin is dependent on de novo synthesis of an intermediary protein(s), since suppression is abrogated by concomitant treatment with cycloheximide (CHX). Destabilization of mRNA transcripts is not the mechanism by which curcumin lowers the levels of mRNA; however, transcripts formed in the presence of curcumin are more stable, as indicated by their slower degradation kinetics. Run-on transcriptional assays demonstrate that curcumin inhibits the transcriptional activity of both genes. Finally, the attenuation of chemokine gene expression is associated with decreased production of chemotactic activity. Together, these findings indicate that while curcumin may post-transcriptionally stabilize mRNA transcripts formed in its presence, the overall reduction in mRNA levels by curcumin is mediated by inhibition of the transcription of chemokine genes.
趋化性细胞因子或趋化因子在骨髓生成的调节中发挥着重要作用。由于骨髓基质细胞产生趋化因子和集落刺激因子（CSF）需要炎症条件，我们研究了姜黄素（一种具有抗炎和抗氧化活性的物质）对小鼠骨髓基质细胞系+/+-1.LDA11中单核细胞趋化蛋白-1（MCP-1或MCP-1/JE）和干扰素诱导蛋白-10kD（IP-10）表达的影响。在用促炎白细胞介素-1α（IL-1α）、干扰素-γ（IFN-γ）、肿瘤坏死因子-α（TNF-α）和内毒素脂多糖（LPS）刺激后，这两种趋化因子在基质细胞中均易于表达。姜黄素可降低所有这些刺激剂所诱导的MCP-1/JE和IP-10 mRNA表达水平。我们对姜黄素对IL-1α诱导的趋化因子表达的调节作用进行了详细分析。姜黄素以剂量和时间依赖性方式抑制这两种趋化因子的mRNA。姜黄素对两种mRNA的抑制作用是可逆的，在去除姜黄素后24小时内可从抑制状态完全恢复。姜黄素对mRNA的抑制作用依赖于中间蛋白的从头合成，因为用环己酰亚胺（CHX）同时处理可消除这种抑制作用。mRNA转录本的不稳定不是姜黄素降低mRNA水平所采用的机制；然而，如降解动力学较慢所示，在姜黄素存在下形成的转录本更稳定。核转录分析表明，姜黄素抑制这两个基因的转录活性。最后，趋化因子基因表达的减弱与趋化活性的产生减少有关。总之，这些发现表明，虽然姜黄素可能在转录后使在其存在下形成的mRNA转录本稳定，但姜黄素使mRNA水平总体降低是通过抑制趋化因子基因的转录介导的。
