Geldanamycin inhibits the production of inflammatory cytokines in activated macrophages by reducing the stability and translation of cytokine transcripts.
Geldanamycin inhibits the production of inflammatory cytokines in activated macrophages by reducing the stability and translation of cytokine transcripts.
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DOI：
10.1002/art.10780
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发表时间：
2003-02
影响因子：
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通讯作者：
S. Wax;M. Piecyk;B. Maritim;P. Anderson
中科院分区：
文献类型：
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作者：
S. Wax;M. Piecyk;B. Maritim;P. Anderson
目的热休克蛋白90（Hsp 90）在促进炎症细胞因子产生的细胞内信号通路中起着重要作用。格尔德霉素（GD）是一种苯醌安莎霉素，抑制热休克蛋白90的功能。GD抑制活化巨噬细胞中肿瘤坏死因子α（TNF α）的产生，并抑制啮齿动物中抗炎药诱导的关节炎和实验性过敏性脑脊髓炎的进展。GD已被用于研究Hsp 90调节炎性细胞因子产生的机制。方法在GD存在或不存在的情况下，用脂多糖激活巨噬细胞系RAW 264.7（或原代腹腔巨噬细胞）。GD对炎症细胞因子信使RNA（mRNA）的转录、稳定性和翻译的影响分别使用核连续测定、mRNA衰变测定和蔗糖梯度多核糖体谱来确定。结果GD能有效抑制活化巨噬细胞产生TNF α、IL-6和IL-1 β。虽然GD没有显着减少炎症细胞因子mRNA的转录，它显着降低这些转录的稳定性。多核糖体谱表明GD还抑制TNF α和IL-6转录物的翻译。这些作用可能部分是由于抑制p38丝裂原活化蛋白激酶，一种已知调节炎性细胞因子转录物的稳定性和翻译的激酶。结论Hsp 90在炎症细胞因子的转录后调控中起重要作用。
OBJECTIVE Heat-shock protein 90 (Hsp90) is critical in the intracellular signaling pathways that promote inflammatory cytokine production. Geldanamycin (GD) is a benzoquinone ansamycin that inhibits the function of Hsp90. GD inhibits the production of tumor necrosis factor alpha (TNFalpha) in activated macrophages and suppresses the progression of adjuvant-induced arthritis and experimental allergic encephalomyelitis in rodents. GD has been used to investigate the mechanisms by which Hsp90 regulates inflammatory cytokine production. METHODS The macrophage cell line RAW264.7 (or primary peritoneal macrophages) was activated with lipopolysaccharide in the absence or presence of GD. The effect of GD on the transcription, stability, and translation of inflammatory cytokine messenger RNA (mRNA) was determined using nuclear run-on assays, mRNA decay assays, and sucrose gradient polysome profiles, respectively. RESULTS Our data revealed that GD potently inhibits the production of TNFalpha, interleukin-6 (IL-6), and IL-1beta in activated macrophages. Although GD did not significantly reduce the transcription of inflammatory cytokine mRNA, it significantly decreased the stability of these transcripts. Polysome profiles indicated that GD also inhibited the translation of TNFalpha and IL-6 transcripts. These effects may be due, in part, to inhibition of p38 mitogen-activated protein kinase, a kinase known to regulate the stability and translation of inflammatory cytokine transcripts. CONCLUSION These results indicate that the function of Hsp90 is important in the posttranscriptional control of inflammatory cytokine production.