Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, and Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio 44195, USA.
J Biol Chem. 2011 Oct 21;286(42):36709-23. doi: 10.1074/jbc.M111.291492. Epub 2011 Aug 30.
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 MKK3 or 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.
白细胞介素 13（IL-13）是一种 Th2 细胞因子，可促进原代人单核细胞的选择性激活（M2 极化）。我们的研究已经对人单核细胞/巨噬细胞中 IL-13 刺激反应的功能性 IL-13 受体复合物和下游信号事件进行了特征描述。在本报告中，我们提供了证据表明，IL-13 诱导一种 Src 家族酪氨酸激酶的激活，该激酶对于 IL-13 诱导的 M2 基因表达（包括 15-脂氧合酶（15-LO））是必需的。我们的数据表明，Src 激酶活性通过上游激酶 MKK3 或 MKK6 调节 IL-13 诱导的 p38 MAPK 酪氨酸磷酸化。我们的发现还揭示了与 IL-13 受体相关的酪氨酸激酶 Jak2 对于 Src 激酶以及 p38 MAPK 的激活都是必需的。此外，我们发现 Src 酪氨酸激酶介导的 p38 MAPK 的激活对于原代人单核细胞/巨噬细胞中 Stat1 和 Stat3 丝氨酸 727 的磷酸化是必需的。进一步的研究确定 Hck 是一种特定的 Src 家族成员，被 IL-13 刺激并参与调节 p38 MAPK 的激活和 p38 MAPK 介导的 15-LO 表达。最后，我们表明 Hck 调节其他选择性激活状态（M2）特异性基因（甘露糖受体、MAO-A 和 CD36）的表达，因此可以得出结论，Hck 是控制原代人单核细胞/巨噬细胞中基因表达的关键调节因子。
