Immunity and Infection Research Centre, Vancouver Coastal Health Research Institute, Vancouver, British Columbia, Canada.
J Biol Chem. 2012 Nov 2;287(45):38020-7. doi: 10.1074/jbc.M112.348599. Epub 2012 Sep 6.
Production of the proinflammatory cytokine TNFα by activated macrophages is an important component of host defense. However, TNFα production must be tightly controlled to avoid pathological consequences. The anti-inflammatory cytokine IL-10 inhibits TNFα mRNA expression through activation of the STAT3 transcription factor pathway and subsequent expression of STAT3-dependent gene products. We hypothesized that IL-10 must also have more rapid mechanisms of action and show that IL-10 rapidly shifts existing TNFα mRNA from polyribosome-associated polysomes to monosomes. This translation suppression requires the presence of SHIP1 (SH2 domain-containing inositol 5'-phosphatase 1) and involves inhibition of Mnk1 (MAPK signal-integrating kinase 1). Furthermore, activating SHIP1 using a small-molecule agonist mimics the inhibitory effect of IL-10 on Mnk1 phosphorylation and TNFα translation. Our data support the existence of an alternative STAT3-independent pathway through SHIP1 for IL-10 to regulate TNFα translation during the anti-inflammatory response.
激活的巨噬细胞产生促炎细胞因子 TNFα 是宿主防御的重要组成部分。然而，必须严格控制 TNFα 的产生，以避免病理性后果。抗炎细胞因子 IL-10 通过激活 STAT3 转录因子途径和随后表达 STAT3 依赖性基因产物来抑制 TNFα mRNA 的表达。我们假设 IL-10 也必须具有更快的作用机制，并表明 IL-10 可迅速将现有的 TNFα mRNA 从多核糖体相关的多核糖体转移到单核糖体。这种翻译抑制需要 SHIP1（含 SH2 结构域的肌醇 5'-磷酸酶 1）的存在，并涉及对 Mnk1（MAPK 信号整合激酶 1）的抑制。此外，使用小分子激动剂激活 SHIP1 可模拟 IL-10 对 Mnk1 磷酸化和 TNFα 翻译的抑制作用。我们的数据支持存在一种替代的 STAT3 独立途径，通过 SHIP1，IL-10 可以在抗炎反应中调节 TNFα 的翻译。
