Hck Is a Key Regulator of Gene Expression in Alternatively Activated Human Monocytes
Hck Is a Key Regulator of Gene Expression in Alternatively Activated Human Monocytes
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DOI：
10.1074/jbc.m111.291492
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发表时间：
2011-10-21
影响因子：
4.8
通讯作者：
Cathcart, Martha K.
中科院分区：
文献类型：
--
作者：
Bhattacharjee, Ashish;Pal, Srabani;Cathcart, Martha K.
IL-13是一种Th 2细胞因子，可促进原代人单核细胞的交替激活（M2极化）。我们的研究已经表征了功能性IL-13受体复合物和响应于在交替活化的单核细胞/巨噬细胞中的IL-13刺激的下游信号传导事件。在这份报告中，我们提出的证据表明，IL-13诱导激活的Src家族酪氨酸激酶，这是必需的IL-13诱导M2基因表达，包括15-脂氧合酶（15-LO）。我们的数据表明Src激酶活性通过上游激酶MKK 3或MKK 6调节IL-13诱导的p38 MAPK酪氨酸磷酸化。我们的研究结果还表明，IL-13受体相关的酪氨酸激酶Jak 2的Src激酶以及p38 MAPK的激活所需的。此外，我们发现，Src酪氨酸激酶介导的p38 MAPK的激活是必需的Stat 1和Stat 3丝氨酸727磷酸化在交替激活的单核细胞/巨噬细胞。另外的研究鉴定Hck为特异性Src家族成员，其被IL-13刺激并参与调节p38 MAPK活化和p38 MAPK介导的15-LO表达。最后，我们表明，HCK调节其他替代状态（M2）特异性基因（甘露糖受体，MAO-A，和CD 36）的表达，因此得出结论，HCK作为一个关键的调节器控制基因表达在交替激活的单核细胞/巨噬细胞。
IL-13 is a Th2 cytokine that promotes alternative activation (M2 polarization) in primary human monocytes. Our studies have characterized the functional IL-13 receptor complex and the downstream signaling events in response to IL-13 stimulation in alternatively activated monocytes/macrophages. In this report, we present evidence that IL-13 induces the activation of a Src family tyrosine kinase, which is required for IL-13 induction of M2 gene expression, including 15-lipoxygenase (15-LO). Our data show that Src kinase activity regulates IL-13-induced p38 MAPK tyrosine phosphorylation via the upstream kinases MKK3or MKK6. Our findings also reveal that the IL-13 receptor-associated tyrosine kinase Jak2 is required for the activation of both Src kinase as well as p38 MAPK. Further, we found that Src tyrosine kinase-mediated activation of p38 MAPK is required for Stat1 and Stat3 serine 727 phosphorylation in alternatively activated monocytes/macrophages. Additional studies identify Hck as the specific Src family member, stimulated by IL-13 and involved in regulating both p38 MAPK activation and p38 MAPK-mediated 15-LO expression. Finally we show that the Hck regulates the expression of other alternative state (M2)-specific genes (Mannose receptor, MAO-A, and CD36) and therefore conclude that Hck acts as a key regulator controlling gene expression in alternatively activated monocytes/macrophages.