Targeted inhibition of heat shock protein 90 suppresses tumor necrosis factor-α and ameliorates murine intestinal inflammation.
Targeted inhibition of heat shock protein 90 suppresses tumor necrosis factor-α and ameliorates murine intestinal inflammation.
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DOI：
10.1097/01.mib.0000442839.28664.75
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发表时间：
2014-04
影响因子：
4.9
通讯作者：
de Zoeten EF
中科院分区：
文献类型：
--
作者：
Collins CB;Strassheim D;Aherne CM;Yeckes AR;Jedlicka P;de Zoeten EF
炎症性肠病是一种慢性肠道炎症性疾病，被认为是免疫反应失调的反映。尽管基于抗体的肿瘤坏死因子-α (TNF-α)抑制已经为许多炎症性肠病患者提供了缓解，但这些疗法要么在患者亚群中无效，要么随着时间的推移而失去疗效，留下了对替代疗法的未满足需求。鉴于热休克反应在调节炎症反应中的关键作用，本研究提出确定选择性抑制热休克蛋白90 （HSP90）对肠道炎症的影响。通过多种炎症性肠病的临床前小鼠模型，我们证明了复方新生物素选择性抑制HSP90 c端atp酶的有效抗炎作用。新生素减毒葡聚糖硫酸钠通过抑制炎性细胞因子分泌（包括TNF-α）诱导结肠炎和cd45rb高过继性结肠炎。体外实验表明，通过细胞内细胞因子染色和酶联免疫吸附法检测，经新生物素处理的CD4+ T细胞产生的TNF-α显著减少。Western blot结果显示，这与Jurkat T细胞中核因子-κB荧光素酶活性的降低和核p65易位的显著减少相对应。最后，为了验证新生霉素的抗tnf作用，我们给20周龄TNFΔARE小鼠皮下注射新生霉素2周。该模型具有高水平的循环TNF-α，并表现为自发性跨壁节段性回肠炎。新生物素治疗显著减少回肠固有层炎症细胞浸润。新生物素抑制HSP90提供了一种抑制炎症细胞因子的新方法，没有发展耐受性的潜力，限制了目前基于抗体的方法。
Inflammatory bowel diseases are chronic intestinal inflammatory diseases thought to reflect a dysregulated immune response. Although antibody-based inhibition of tumor necrosis factor-α (TNF-α) has provided relief to many inflammatory bowel diseases patients, these therapies are either ineffective in a patient subset or lose their efficacy over time, leaving an unmet need for alternatives. Given the critical role of the heat shock response in regulating inflammation, this study proposed to define the impact of selective inhibition of heat shock protein 90 (HSP90) on intestinal inflammation. Using multiple preclinical mouse models of inflammatory bowel diseases, we demonstrate a potent anti-inflammatory effect of selective inhibition of the HSP90 C-terminal ATPase using the compound novobiocin. Novobiocin-attenuated dextran sulfate sodium-induced colitis and CD45RBhigh adoptive-transfer colitis through the suppression of inflammatory cytokine secretion, including TNF-α. In vitro assays demonstrate that CD4+ T cells treated with novobiocin produced significantly less TNF-α measured by intracellular cytokine staining and by enzyme-linked immunosorbent assay. This corresponded to significantly decreased nuclear p65 translocation by Western blot and a decrease in nuclear factor-κB luciferase activity in Jurkat T cells. Finally, to verify the anti-TNF action of novobiocin, 20-week-old TNFΔARE mice were treated for 2 weeks with subcutaneous administration of novobiocin. This model has high levels of circulating TNF-α and exhibits spontaneous transmural segmental ileitis. Novobiocin treatment significantly reduced inflammatory cell infiltrate in the ileal lamina propria. HSP90 inhibition with novobiocin offers a novel method of inflammatory cytokine suppression without potential for the development of tolerance that limits current antibody-based methods.