Kim Hee-Jung, Hart Judy, Knatz Nina, Hall Mark W, Wewers Mark D
Division of Pulmonary and Critical Care Medicine, and Davis Heart and Lung Research Institute, Ohio State University, Columbus, OH 43210, USA.
J Immunol. 2004 Apr 15;172(8):4948-55. doi: 10.4049/jimmunol.172.8.4948.
ProIL-1 beta processing by IL-1 beta-converting enzyme (ICE) and the subsequent release of mature IL-1 beta 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 JAK1 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-1 beta processing and release.
白细胞介素-1β转换酶（ICE）对前白细胞介素-1β的加工以及随后成熟白细胞介素-1β的释放，是单核细胞/巨噬细胞对病原体反应中受到高度调控的事件。这个过程通过组成型表达的45 kDa ICE前体（proICE）的激活以可控方式发生。为了表征人类单核细胞/巨噬细胞中参与ICE调控的信号通路，我们在经典信号通路的特异性抑制剂存在的情况下分析了ICE的激活情况。尽管脂多糖（LPS）诱导的ICE活性不受细胞外信号调节激酶、p38激酶或磷酸肌醇3激酶阻断的显著影响，但Janus激酶3（JAK3）抑制却产生了LPS诱导的ICE活性的显著剂量依赖性增强。IL-4（其使用JAK1和JAK3信号传导）抑制LPS诱导的ICE活性以及JAK3基因敲除巨噬细胞具有增强的LPS诱导的ICE激活这一发现，都证明了JAK3的抑制作用。为了理解JAK3如何下调单核细胞中LPS诱导的ICE活性，我们推测JAK3信号传导增强白细胞介素-10（IL-10）的产生。支持该模型的证据如下：LPS诱导的IL-10表达与ICE失活同步，IL-4诱导IL-10释放，外源性IL-10抑制LPS诱导的ICE活性，一种中和性IL-10抗体增加LPS诱导的ICE活性，最后，JAK3基因敲除巨噬细胞显示出显著降低的LPS诱导的IL-10产生。这些发现支持了一个模型，即JAK3信号传导增强IL-10的产生，从而导致ICE激活的下调以及白细胞介素-1β加工和释放的抑制。
