The role of TRKA signaling in IL-10 production by apoptotic tumor cell-activated macrophages
The role of TRKA signaling in IL-10 production by apoptotic tumor cell-activated macrophages
复制标题
DOI：
10.1038/onc.2012.77
复制
发表时间：
2013-01-31
期刊：
影响因子：
8
通讯作者：
Bruene, B.
中科院分区：
文献类型：
--
作者：
Ley, S.;Weigert, A.;Bruene, B.
肿瘤相关巨噬细胞(TAM)是肿瘤中的主要支持成分。巨噬细胞(M(1))吸引和分化为一种肿瘤促进表型的机制正在研究中，该表型的特征是产生明显的白介素10(IL-10)。我们报道，垂死癌细胞的上清诱导原代人类MOS大量释放IL-10，这依赖于通过酪氨酸激酶受体A(TrkA或神经营养性酪氨酸激酶受体1(NTRK1))的信号。从机制上讲，凋亡癌细胞释放的鞘氨醇-1-磷酸通过S1P受体信号触发src依赖的胞浆TrkA穿梭到质膜。质膜相关TrkA由结构性自分泌神经生长因子激活，利用磷脂酰肌醇3-激酶(PI3K)/AKT和p38丝裂原活化蛋白激酶(MAPK)信号途径诱导IL-10。有趣的是，从原发小鼠乳腺癌组织中分离的TAMs产生细胞因子需要TrkA依赖的信号。除IL-10外，该途径还可促进IL-6、肿瘤坏死因子-α(TNF-α)和单核细胞趋化蛋白-1(MCP-1)的分泌，提示与癌症相关的炎症反应有关。我们的发现强调了一个微调的调控系统，包括S1P依赖的TrkA运输，在体外和体内执行样的细胞功能。Oncogene(2013)32,631-640；doi：10.1038/onc.2012.77；2012年3月12日在线发布
Tumor-associated macrophages (TAMs) are a major supportive component within neoplasms. Mechanisms of macrophage (M(1)) attraction and differentiation to a tumor-promoting phenotype, which is characterized by pronounced interleukin (IL)-10 production, are under investigation. We report that supernatants of dying cancer cells induced substantial IL-10 release from primary human MOs, dependent on signaling through tyrosine kinase receptor A (TRKA or neurotrophic tyrosine kinase receptor type 1 (NTRK1)). Mechanistically, sphingosine-1-phosphate (SIP) release from apoptotic cancer cells triggered src-dependent shuttling of cytosolic TRKA to the plasma membrane via S1P receptor signaling. Plasma membrane-associated TRKA, which was activated by constitutively autocrine secreted nerve growth factor, used phosphatidylinositol 3-kinase (PI3K)/AKT and p38 mitogen-activated protein kinase (MAPK) signaling to induce IL-10. Interestingly, TRKA-dependent signaling was required for cytokine production by TAMs isolated from primary murine breast cancer tissue. Besides IL-10, this pathway initiated secretion of IL-6, tumor necrosis factor-alpha (TNF-alpha) and monocyte chemotactic protein-1 (MCP-1), indicating relevance in cancer-associated inflammation. Our findings highlight a fine-tuned regulatory system including S1P-dependent TRKA trafficking for executing TAM-like cell function in vitro as well as in vivo. Oncogene (2013) 32, 631-640; doi:10.1038/onc.2012.77; published online 12 March 2012