Suppressors of Cytokine Signaling (SOCS)1 and SOCS3 Proteins Are Mediators of Interleukin-10 Modulation of Inflammatory Responses Induced by Chlamydia muridarum and Its Major Outer Membrane Protein (MOMP) in Mouse J774 Macrophages
Suppressors of Cytokine Signaling (SOCS)1 and SOCS3 Proteins Are Mediators of Interleukin-10 Modulation of Inflammatory Responses Induced by Chlamydia muridarum and Its Major Outer Membrane Protein (MOMP) in Mouse J774 Macrophages
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DOI：
10.1155/2020/7461742
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发表时间：
2020-06-24
影响因子：
4.6
通讯作者：
Dennis, Vida A.
中科院分区：
文献类型：
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作者：
Duncan, Skyla A.;Sahu, Rajnish;Dennis, Vida A.
衣原体疾病的免疫病理被广谱炎症介质加剧，我们报道了巨噬细胞中IL-10抑制炎症介质。然而，诱导炎症介质的衣原体蛋白片段和IL-10抑制它们的机制尚不清楚。我们假设衣原体主要外膜蛋白（MOMP）介导其发病机制，细胞因子信号抑制因子（SOCS）1和SOCS3蛋白是IL-10抑制作用的介质。我们的假设通过将小鼠J774巨噬细胞暴露于衣原体刺激物（活衣原体和MOMP）中来验证，这些衣原体刺激物有或没有IL-10。MOMP显著诱导了几种炎症介质（IL-6、IL-12p40、CCL5、CXCL10），这些炎症介质被IL-10剂量依赖性地抑制。衣原体兴奋剂诱导SOCS1和SOCS3 mRNA基因转录本和蛋白表达，其中SOCS3表达量增加。值得注意的是，IL-10通过降低SOCS1和增加SOCS3来相互调节它们的表达。MAPK通路的特异性抑制表明p38、JNK和MEK1/2是诱导炎症介质以及SOCS1和SOCS3所必需的。衣原体兴奋剂通过增强nos2 （M1标记物）的表达而诱发M1促炎表型，而IL-10通过增加mrc1和arg1 （M2标记物）的表达和降低SOCS1/SOCS3的比值，使M1促炎表型向M2促炎表型倾斜。内源性产生的IL-10的中和增加了炎症介质的分泌，降低了SOCS3的表达，并使衣原体M1向M2表型倾斜。抑制蛋白酶体降解可通过抑制SOCS1和SOCS3的表达以及失调其STAT1和STAT3转录因子，增加TNF，但降低IL-10、CCL5和CXCL10的分泌。我们的数据显示，SOCS1和SOCS3是IL-10抑制作用的调节因子，并强调SOCS蛋白是IL-10控制衣原体和其他细菌性炎症疾病炎症的治疗靶点。
The immunopathology of chlamydial diseases is exacerbated by a broad-spectrum of inflammatory mediators, which we reported are inhibited by IL-10 in macrophages. However, the chlamydial protein moiety that induces the inflammatory mediators and the mechanisms by which IL-10 inhibits them are unknown. We hypothesized thatChlamydiamajor outer membrane protein (MOMP) mediates its disease pathogenesis, and the suppressor of cytokine signaling (SOCS)1 and SOCS3 proteins are mediators of the IL-10 inhibitory actions. Our hypothesis was tested by exposing mouse J774 macrophages to chlamydial stimulants (liveChlamydia muridarumand MOMP) with and without IL-10. MOMP significantly induced several inflammatory mediators (IL-6, IL-12p40, CCL5, CXCL10), which were dose-dependently inhibited by IL-10. Chlamydial stimulants induced the mRNA gene transcripts and protein expression of SOCS1 and SOCS3, with more SOCS3 expression. Notably, IL-10 reciprocally regulated their expression by reducing SOCS1 and increasing SOCS3. Specific inhibitions of MAPK pathways revealed that p38, JNK, and MEK1/2 are required for inducing inflammatory mediators as well as SOCS1 and SOCS3. Chlamydial stimulants triggered an M1 pro-inflammatory phenotype evidently by an enhanced nos2 (M1 marker) expression, which was skewed by IL-10 towards a more M2 anti-inflammatory phenotype by the increased expression of mrc1 and arg1 (M2 markers) and the reduced SOCS1/SOCS3 ratios. Neutralization of endogenously produced IL-10 augmented the secretion of inflammatory mediators, reduced SOCS3 expression, and skewed the chlamydial M1 to an M2 phenotype. Inhibition of proteasome degradation increased TNF but decreased IL-10, CCL5, and CXCL10 secretion by suppressing SOCS1 and SOCS3 expressions and dysregulating their STAT1 and STAT3 transcription factors. Our data show that SOCS1 and SOCS3 are regulators of IL-10 inhibitory actions, and underscore SOCS proteins as therapeutic targets for IL-10 control of inflammation forChlamydiaand other bacterial inflammatory diseases.