Wang Lu, Tassiulas Ioannis, Park-Min Kyung-Hyun, Reid Alicia C, Gil-Henn Hava, Schlessinger Joseph, Baron Roland, Zhang J Jillian, Ivashkiv Lionel B
Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, New York 10021, USA.
Nat Immunol. 2008 Feb;9(2):186-93. doi: 10.1038/ni1548. Epub 2007 Dec 16.
Immunoreceptor tyrosine-based activation motif (ITAM)-coupled receptors modulate the amplitude and nature of macrophage responses to Toll-like receptor and cytokine receptor stimulation. However, the molecular mechanisms enabling this receptor crosstalk are not known. Here we investigated the function of the calcium-dependent kinases CaMK and Pyk2 'downstream' of ITAM-associated receptors in the regulation of cytokine-induced activation of Jak kinases and STAT transcription factors. CaMK and Pyk2 relayed signals from integrins and the ITAM-containing adaptor DAP12 to augment interleukin 10- and interferon-alpha-induced Jak activation and STAT1-dependent gene expression. CaMK inhibition suppressed STAT1-mediated interferon-alpha signaling in a mouse model of systemic lupus erythematosus. Our results associate Pyk2 and Jak kinases with the linkage of signals emanating from cytokine and heterologous ITAM-dependent receptors.
基于免疫受体酪氨酸的激活基序（ITAM）偶联受体可调节巨噬细胞对Toll样受体和细胞因子受体刺激的反应幅度及性质。然而，促成这种受体串扰的分子机制尚不清楚。在此，我们研究了ITAM相关受体“下游”的钙依赖性激酶CaMK和Pyk2在调节细胞因子诱导的Jak激酶激活和STAT转录因子方面的功能。CaMK和Pyk2传递来自整合素和含ITAM的接头蛋白DAP12的信号，以增强白细胞介素10和干扰素α诱导的Jak激活以及STAT1依赖性基因表达。在系统性红斑狼疮小鼠模型中，CaMK抑制作用可抑制STAT1介导的干扰素α信号传导。我们的研究结果将Pyk2和Jak激酶与细胞因子和异源ITAM依赖性受体发出的信号联系起来。
