Macrophage-secreted cytokines drive pancreatic acinar-to-ductal metaplasia through NF-κB and MMPs.
Macrophage-secreted cytokines drive pancreatic acinar-to-ductal metaplasia through NF-κB and MMPs.
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DOI：
10.1083/jcb.201301001
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发表时间：
2013-08-05
期刊：
影响因子：
--
通讯作者：
Storz P
中科院分区：
文献类型：
--
作者：
Liou GY;Döppler H;Necela B;Krishna M;Crawford HC;Raimondo M;Storz P
炎症反应中浸润胰腺的巨噬细胞通过分泌激活NF-κB信号传导和基质金属蛋白酶表达的细胞因子诱导细胞转分化。在炎症反应中，胰腺腺泡细胞可经历腺泡-导管化生（ADM），这是一种诱导转分化为导管样表型的重编程事件，在额外致癌刺激的背景下，有助于胰腺癌的发展。胰腺炎诱导ADM的信号机制在很大程度上是不确定的。我们的研究结果提供了证据，巨噬细胞浸润胰腺驱动这一转分化过程。我们确定巨噬细胞分泌的炎症细胞因子RANTES和肿瘤坏死因子α（TNF）作为这种信号传导的介质。RANTES和TNF均通过激活核因子κB及其参与调节细胞存活、增殖和细胞外基质降解的靶基因诱导ADM。特别是，我们确定了基质金属蛋白酶（MMPs）作为驱动ADM的靶点，并提供了体内数据，表明MMP抑制剂可有效地用于阻断胰腺炎诱导的ADM治疗。
Macrophages infiltrating the pancreas in response to inflammation induce cellular transdifferentiation by secreting cytokines that activate NF-κB signaling and matrix metalloproteinase expression. In response to inflammation, pancreatic acinar cells can undergo acinar-to-ductal metaplasia (ADM), a reprogramming event that induces transdifferentiation to a ductlike phenotype and, in the context of additional oncogenic stimulation, contributes to development of pancreatic cancer. The signaling mechanisms underlying pancreatitis-inducing ADM are largely undefined. Our results provide evidence that macrophages infiltrating the pancreas drive this transdifferentiation process. We identify the macrophage-secreted inflammatory cytokines RANTES and tumor necrosis factor α (TNF) as mediators of such signaling. Both RANTES and TNF induce ADM through activation of nuclear factor κB and its target genes involved in regulating survival, proliferation, and degradation of extracellular matrix. In particular, we identify matrix metalloproteinases (MMPs) as targets that drive ADM and provide in vivo data suggesting that MMP inhibitors may be efficiently applied to block pancreatitis-induced ADM in therapy.
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