Beta Interferon Production Is Regulated by p38 Mitogen-Activated Protein Kinase in Macrophages via both MSK1/2- and Tristetraprolin-Dependent Pathways.
Beta Interferon Production Is Regulated by p38 Mitogen-Activated Protein Kinase in Macrophages via both MSK1/2- and Tristetraprolin-Dependent Pathways.
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DOI：
10.1128/mcb.00454-16
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发表时间：
2017-01-01
影响因子：
5.3
通讯作者：
Arthur JSC
中科院分区：
文献类型：
--
作者：
McGuire VA;Rosner D;Ananieva O;Ross EA;Elcombe SE;Naqvi S;van den Bosch MMW;Monk CE;Ruiz-Zorrilla Diez T;Clark AR;Arthur JSC
β干扰素（IFN-β）的自分泌或旁分泌信号传导对于巨噬细胞对病原体相关分子模式的许多反应是必不可少的。这种反馈回路有助于对感染因子的病理反应，因此受到严格调控。我们在这里证明，巨噬细胞表达的IFN-β是负调控的丝裂原和应激激活激酶1和2（MSK 1/2）。脂多糖（LPS）诱导的IFN-β表达在MSK 1/2敲除小鼠和巨噬细胞中均升高。尽管MSK 1和-2促进抗炎细胞因子白细胞介素10的表达，但它并没有强烈地促进MSK调节IFN-β表达的能力。相反，MSK 1和-2通过诱导双特异性磷酸酶1（DUSP 1）抑制IFN-β表达，DUSP 1使促分裂原活化蛋白激酶p38和Jun N-末端蛋白激酶（JNK）去磷酸化并失活。LPS诱导的p38和JNK活化延长、下游转录因子磷酸化以及IFN-β mRNA和蛋白的过表达在MSK 1/2和DUSP 1敲除巨噬细胞中相似。IFN-β的过表达涉及两种不同的机制：第一，JNK介导的c-jun激活，其结合IFN-β启动子，第二，p38介导的mRNA去稳定因子tristetraprolin失活，我们显示其能够靶向IFN-β mRNA。
Autocrine or paracrine signaling by beta interferon (IFN-β) is essential for many of the responses of macrophages to pathogen-associated molecular patterns. This feedback loop contributes to pathological responses to infectious agents and is therefore tightly regulated. We demonstrate here that macrophage expression of IFN-β is negatively regulated by mitogen- and stress-activated kinases 1 and 2 (MSK1/2). Lipopolysaccharide (LPS)-induced expression of IFN-β was elevated in both MSK1/2 knockout mice and macrophages. Although MSK1 and -2 promote the expression of the anti-inflammatory cytokine interleukin 10, it did not strongly contribute to the ability of MSKs to regulate IFN-β expression. Instead, MSK1 and -2 inhibit IFN-β expression via the induction of dual-specificity phosphatase 1 (DUSP1), which dephosphorylates and inactivates the mitogen-activated protein kinases p38 and Jun N-terminal protein kinase (JNK). Prolonged LPS-induced activation of p38 and JNK, phosphorylation of downstream transcription factors, and overexpression of IFN-β mRNA and protein were similar in MSK1/2 and DUSP1 knockout macrophages. Two distinct mechanisms were implicated in the overexpression of IFN-β: first, JNK-mediated activation of c-jun, which binds to the IFN-β promoter, and second, p38-mediated inactivation of the mRNA-destabilizing factor tristetraprolin, which we show is able to target the IFN-β mRNA.