Activated signal transducer and activator of transcription-3 (STAT3) is a poor regulator of tumour necrosis factor-α production by human monocytes
Activated signal transducer and activator of transcription-3 (STAT3) is a poor regulator of tumour necrosis factor-α production by human monocytes
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DOI：
10.1111/j.1365-2249.2006.03291.x
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发表时间：
2007-03-01
影响因子：
4.6
通讯作者：
Hart, P. H.
中科院分区：
文献类型：
--
作者：
Prele, C. M.;Keith-Magee, A. L.;Hart, P. H.
信号转导器和转录激活剂 3 (STAT3) 的激活与实验动物、小鼠骨髓细胞和巨噬细胞系中炎症过程的抑制有关。因此，调控 STAT3 活性可能是人类炎症性疾病药物干预的焦点。然而，STAT3 减少活化的人单核细胞和巨噬细胞产生炎症介质的能力尚未得到充分表征。为了证实这一点，我们使用最近优化的腺病毒方法来研究过表达的 STAT3 或转录失活突变体 STAT3 在脂多糖 (LPS) 刺激的人单核细胞中的作用。 LPS 激活的 STAT3 并不直接调节 kappa B α 抑制剂 (I kappa B α) 的激活或肿瘤坏死因子 (TNF)-α 的产生，这一过程依赖于核因子 kappa B (NF kappa B) 的转录活性，尽管 STAT3 的转录活性有助于白细胞介素 (IL)-10 抑制 LPS 诱导的 TNF-α 水平的机制。这与感染表达突变体 STAT3 的腺病毒的单核细胞中 IL-10 诱导细胞因子信号传导抑制因子 3 (SOCS3) 的有效阻断形成对比。这些结果表明，STAT3 激活不能直接调节人单核细胞中的 LPS 信号传导，并且仅代表 IL-10 抑制激活的人单核细胞产生 TNF-α 的部分机制。这项研究的结论是，仅对 STAT3 转录活性进行药理学操作不足以控制人类 NF kappa B 相关炎症。
Signal transducer and activator of transcription-3 (STAT3) activation has been associated with suppressed inflammatory processes in experimental animals, murine myeloid cells and macrophage cell lines. Manipulation of STAT3 activity may therefore be a focus for pharmacological intervention of inflammatory diseases in humans. However, the ability of STAT3 to reduce the production of inflammatory mediators by activated human monocytes and macrophages has been characterized inadequately. To establish this, we used a recently optimized adenoviral approach to study the effect of overexpressed STAT3 or a transcriptionally inactive mutant STAT3 in lipopolysaccharide (LPS)-stimulated human monocytes. STAT3 activated by LPS did not directly regulate inhibitor of kappa B alpha (I kappa B alpha) activation or tumour necrosis factor (TNF)-alpha production, a process dependent on the transcriptional activity of nuclear factor kappa B (NF kappa B), although the transcriptional activity of STAT3 contributed to the mechanism by which interleukin (IL)-10 suppressed LPS-induced TNF-alpha levels. This contrasted with the efficient block in IL-10 induction of suppressor of cytokine signalling-3 (SOCS3) in monocytes infected with an adenovirus expressing mutant STAT3. These results indicate that STAT3 activation cannot directly regulate LPS-signalling in human monocytes and represents only part of the mechanism by which IL-10 suppresses TNF-alpha production by activated human monocytes. This study concludes that pharmacological manipulation of STAT3 transcriptional activity alone would be insufficient to control NF kappa B-associated inflammation in humans.