Janus kinase 3 down-regulates lipopolysaccharide-induced IL-1β-converting enzyme activation by autocrine IL-10
Janus kinase 3 down-regulates lipopolysaccharide-induced IL-1β-converting enzyme activation by autocrine IL-10
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DOI：
10.4049/jimmunol.172.8.4948
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发表时间：
2004-04-15
影响因子：
4.4
通讯作者：
Wewers, MD
中科院分区：
文献类型：
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作者：
Kim, HJ;Hart, J;Wewers, MD
IL-1β转换酶(ICE)对ProIL-1β的处理和随后成熟IL-1β的释放是单核/巨噬细胞对病原体反应的高度调控事件。这一过程通过激活组成性表达的45 kDa ICE前体(ProICE)以受控的方式发生。为了研究ICE在人类单核/巨噬细胞中的调节作用，我们分析了经典信号通路的特异性抑制剂对ICE的激活作用。尽管细胞外信号调节蛋白激酶、p38蛋白和3-磷酸肌醇蛋白激酶的阻断对脂多糖诱导的细胞外刺激活性无明显影响，但抑制Janus kinase3(JAK3)可显著增强内毒素诱导的细胞内皮细胞活性，且呈剂量依赖性。IL-4(使用JAM和JAK3信号)抑制内毒素诱导的ICE活性，以及JAK3基因敲除的巨噬细胞增加内毒素诱导的ICE激活的发现，证明了JAK3的抑制作用。为了了解JAK3如何下调内毒素诱导的单核细胞ICE活性，我们假设JAK3信号增强了IL-10的产生。结果表明，IL-10的表达与ICE失活同步，IL-4诱导IL-10的释放，外源性IL-10抑制内毒素诱导的ICE活性，中和性IL-10抗体增强内毒素诱导的ICE活性，JAK3基因敲除的巨噬细胞显著减少内毒素诱导的IL-10的产生。这些发现支持JAK3信号增强IL-10产生的模型，导致下调ICE激活和抑制IL-1β的处理和释放。
ProIL-1beta processing by IL-1beta-converting enzyme (ICE) and the subsequent release of mature IL-1beta are highly regulated events in the monocyte/macrophage response to pathogens. This process occurs in a controlled way through the activation of the constitutively expressed 45-kDa ICE precursor (proICE). To characterize the signaling pathways involved in ICE regulation in human monocytes/macrophages, we analyzed ICE activation in the presence of specific inhibitors of classic signaling pathways. Although LPS-induced ICE activity was not significantly affected by interruption of extracellular signal-regulated kinase, p38 kinase, or phosphoinositol 3-kinase, Janus kinase 3 (JAK3) inhibition produced a significant dose-dependent enhancement of LPS-induced ICE activity. Support for the inhibitory role of JAK3 was shown by the fact that IL-4 (which uses JAM and JAK3 signaling) suppressed LPS-induced ICE activity and by the finding that JAK3 knockout macrophages have increased LPS-induced ICE activation. To understand how JAK3 down-regulates LPS-induced ICE activity in monocytes, we hypothesized that JAK3 signaling enhances IL-10 production. In support of this model we show that LPS-induced IL-10 expression was synchronous with ICE deactivation, IL-4 induced the release of IL-10, exogenous IL-10 suppressed LPS-induced ICE activity, a neutralizing IL-10 Ab increased LPS-induced ICE activity, and, finally, JAK3 knockout macrophages displayed significantly reduced LPS-induced IL-10 production. These findings support a model in which JAK3 signaling enhances IL-10 production leading to down-regulation of ICE activation and suppression of IL-1beta processing and release.