Inhibition of JAKs in macrophages increases lipopolysaccharide-induced cytokine production by blocking IL-10-mediated feedback.
Inhibition of JAKs in macrophages increases lipopolysaccharide-induced cytokine production by blocking IL-10-mediated feedback.
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DOI：
10.4049/jimmunol.1200310
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发表时间：
2012-09-15
期刊：
影响因子：
--
通讯作者：
Arthur JS
中科院分区：
文献类型：
--
作者：
Pattison MJ;Mackenzie KF;Arthur JS
巨噬细胞是感染后细胞因子的重要来源。用TLR激动剂刺激巨噬细胞导致TNFα、IL-6和IL-12的分泌，并且这些细胞因子的产生由多个反馈途径控制。巨噬细胞还产生IL-10，其通过JAK/STAT 3依赖性途径抑制巨噬细胞产生促炎细胞因子。我们在此表明，Ruxolitinib，一种最近描述的JAK的选择性抑制剂，在用LPS刺激的小鼠骨髓来源的巨噬细胞中增加TNF、IL-6和IL-12的分泌。这种作用主要是由于其阻断IL-10介导的对巨噬细胞中细胞因子转录的反馈抑制的能力。用第二种结构上不相关的Jak抑制剂托法替尼也获得了类似的结果。此外，LPS诱导IFNβ的产生，其然后能够激活巨噬细胞中的JAK，从而刺激STAT 1磷酸化。IL-10的初始诱导不依赖于JAK信号传导，然而JAK的抑制确实在随后的时间点减少IL-10分泌。这反映了IFNβ反馈环在LPS刺激后维持IL-10转录的需要。除IL-10外，IFNβ还有助于维持IL-6和IL-12的转录。总之，这些结果表明JAK的抑制可增加用TLR 4激动剂刺激的巨噬细胞的炎症潜能。
Macrophages are an important source of cytokines following infection. Stimulation of macrophages with TLR agonists results in the secretion of TNFα, IL-6 and IL-12, and the production of these cytokines is controlled by multiple feedback pathways. Macrophages also produce IL-10, which acts to inhibit pro-inflammatory cytokine production by macrophages via a JAK/STAT3 dependent pathway. We show here that, Ruxolitinib, a recently described selective inhibitor of JAKs, increases TNF, IL-6 and IL-12 secretion in mouse bone marrow derived macrophages stimulated with LPS This effect is largely due to its ability to block IL-10 mediated feedback inhibition on cytokine transcription in macrophages. Similar results were also obtained with a second structurally unrelated Jak inhibitor, Tofacitinib. In addition, LPS induced the production of IFNβ, which was then able to activate JAKs in macrophages resulting in the stimulation of STAT1 phosphorylation. The initial induction of IL-10 was independent of JAK signaling, however inhibition of JAKs did reduce IL-10 secretion at later time points. This reflected a requirement for the IFNβ feedback loop to sustain IL-10 transcription following LPS stimulation. In addition to IL-10, IFNβ also helped sustain IL-6 and IL-12 transcription. Overall, these results suggest that inhibition of JAKs may increase the inflammatory potential of macrophages stimulated with TLR4 agonists.
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I型Interferon自分泌 - 核酸环与树突状细胞的Toll样受体诱导的白介素-12p70分泌有关。
影响因子：
15.3
作者：
Gautier, G;Humbert, M;Deauvieau, F;Scuiller, M;Hiscott, J;Bates, EEM;Trinchieri, G;Caux, C;Garrone, P
通讯作者：
Garrone, P
DOI：
10.1084/jem.170.6.2081
发表时间：
1989-12-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Fiorentino DF;Bond MW;Mosmann TR
通讯作者：
Mosmann TR
影响因子：
5.3
作者：
Beardmore, VA;Hinton, HJ;Arthur, JSC
通讯作者：
Arthur, JSC
影响因子：
4.4
作者：
Kawai, T;Takeuchi, O;Akira, S
通讯作者：
Akira, S
影响因子：
4.8
作者：
Gleason, Catherine E.;Ordureau, Alban;Cohen, Philip
通讯作者：
Cohen, Philip