Suppressor of Cytokine Signaling (SOCS)1 Regulates Interleukin-4 (IL-4)-activated Insulin Receptor Substrate (IRS)-2 Tyrosine Phosphorylation in Monocytes and Macrophages via the Proteasome
Suppressor of Cytokine Signaling (SOCS)1 Regulates Interleukin-4 (IL-4)-activated Insulin Receptor Substrate (IRS)-2 Tyrosine Phosphorylation in Monocytes and Macrophages via the Proteasome
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DOI：
10.1074/jbc.m116.746164
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发表时间：
2016-09-23
影响因子：
4.8
通讯作者：
Heller, Nicola M.
中科院分区：
文献类型：
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作者：
McCormick, Sarah M.;Gowda, Nagaraj;Heller, Nicola M.
过敏性哮喘是由Th 2细胞因子IL-4/-13引发和驱动的慢性肺部疾病。在巨噬细胞中，IL-4/-13结合IL-4受体，其通过胰岛素受体底物（IRS）-2发出信号，诱导M2巨噬细胞分化。M2巨噬细胞与疾病严重程度和肺功能差相关，尽管调节M2极化的机制尚不清楚。IL-4暴露后，细胞因子信号转导抑制因子（SOCS）1在人单核细胞中高度诱导。我们发现，siRNA敲除SOCS 1延长IRS-2酪氨酸磷酸化和增强M2分化，虽然siRNA敲除SOCS 3没有影响。通过免疫共沉淀，我们发现SOCS 1在基线时与IRS-2复合，并且这种关联在IL-4刺激后增加。由于SOCS 1是一种E3泛素连接酶，我们研究了蛋白酶体抑制剂对IL-4诱导的IRS-2磷酸化的影响。蛋白酶体抑制延长IRS-2酪氨酸磷酸化，增加IRS-2的泛素化，并增强M2基因表达。siRNA敲除SOCS 1抑制IRS-2上的泛素积累，尽管siRNA敲除SOCS 3对IRS-2的泛素化没有影响。来自健康和过敏个体的单核细胞显示，SOCS 1在健康单核细胞中被IL-4诱导，但在过敏细胞中不被诱导，而SOCS 3在过敏单核细胞中被高度诱导。健康的单核细胞显示更大的IRS-2的泛素化和较低的M2极化比过敏性单核细胞在响应IL-4刺激。在这里，我们确定SOCS 1作为IL-4诱导的IRS-2信号传导和M2分化的关键负调节因子。我们的研究结果提供了新的见解如何失调的表达SOCS增加过敏性单核细胞的IL-4反应，这可能代表了一个新的治疗途径，用于管理过敏性疾病。
Allergic asthma is a chronic lung disease initiated and driven by Th2 cytokines IL-4/-13. In macrophages, IL-4/-13 bind IL-4 receptors, which signal through insulin receptor substrate (IRS)-2, inducing M2 macrophage differentiation. M2 macrophages correlate with disease severity and poor lung function, although the mechanisms that regulate M2 polarization are not understood. Following IL-4 exposure, suppressor of cytokine signaling (SOCS)1 is highly induced in human monocytes. We found that siRNA knockdown of SOCS1 prolonged IRS-2 tyrosine phosphorylation and enhanced M2 differentiation, although siRNA knockdown of SOCS3 did not affect either. By co-immunoprecipitation, we found that SOCS1 complexes with IRS-2 at baseline, and this association increased after IL-4 stimulation. Because SOCS1 is an E3 ubiquitin ligase, we examined the effect of proteasome inhibitors on IL-4-induced IRS-2 phosphorylation. Proteasomal inhibition prolonged IRS-2 tyrosine phosphorylation, increased ubiquitination of IRS-2, and enhanced M2 gene expression. siRNA knockdown of SOCS1 inhibited ubiquitin accumulation on IRS-2, although siRNA knockdown of SOCS3 had no effect on ubiquitination of IRS-2. Monocytes from healthy and allergic individuals revealed that SOCS1 is induced by IL-4 in healthy monocytes but not allergic cells, whereas SOCS3 is highly induced in allergic monocytes. Healthy monocytes displayed greater ubiquitination of IRS-2 and lower M2 polarization than allergic monocytes in response to IL-4 stimulation. Here, we identify SOCS1 as a key negative regulator of IL-4-induced IRS-2 signaling and M2 differentiation. Our findings provide novel insight into how dysregulated expression of SOCS increases IL-4 responses in allergic monocytes, and this may represent a new therapeutic avenue for managing allergic disease.