Keratinocytes express cytokines and nerve growth factor in response to neuropeptide activation of the ERK1/2 and JNK MAPK transcription pathways.
Keratinocytes express cytokines and nerve growth factor in response to neuropeptide activation of the ERK1/2 and JNK MAPK transcription pathways.
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DOI：
10.1016/j.regpep.2013.08.001
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发表时间：
2013-09-10
影响因子：
--
通讯作者：
Kingery WS
中科院分区：
文献类型：
--
作者：
Shi X;Wang L;Clark JD;Kingery WS
支配皮肤的感觉神经元可以释放神经肽，这些神经肽被认为可以调节细胞增殖、伤口愈合、色素沉着和角质形成细胞的先天免疫反应。虽然神经肽刺激角化细胞产生炎症介质的能力已被证实，但没有关于神经肽激活角化细胞表面受体最终导致介质产生上调的机制的信息。在这项研究中，我们使用角化细胞细胞系鉴定了P物质（SP）和降钙素基因相关肽（CGRP）受体在角化细胞上的存在，并检测了SP和CGRP刺激对角化细胞神经肽信号、细胞增殖和白细胞介素-1β (IL-1)、白细胞介素-6 （IL-6）、肿瘤坏死因子α (TNF)和神经生长因子（NGF）表达的影响。神经肽刺激导致角化细胞中神经肽受体表达上调，角化细胞分泌SP和CGRP显著增加，提示可能存在自分泌或旁分泌刺激作用，神经肽信号放大。SP和CGRP浓度依赖性地刺激细胞增殖以及角化细胞中炎症因子和NGF的表达和分泌。SP还激活了角质形成细胞中所有3个丝裂原活化蛋白激酶（MAPK）和核因子κB （NFκB）家族，而CGRP仅激活了p38和细胞外信号相关激酶1/2 (ERK1/2) MAPK。ERK1/2和JNK抑制剂可逆转角化细胞中神经肽刺激的炎症介质产生。目前的研究是第一个观察到；1) CGRP刺激角化细胞表达CGRP及其受体复合物，2)SP和CGRP刺激角化细胞IL-6和TNF分泌，3)SP激活了所有三个MAPK家族和角化细胞中NFκB转录信号通路，4)SP和CGRP刺激角化细胞中炎症介质的产生依赖于ERK1/2和JNK的激活。这些研究提供的证据表明，ERK1/2和JNK信号的破坏可能是一种潜在的有效治疗炎症性皮肤病和疼痛综合征介导的过度的感觉神经元-角化细胞信号。
Sensory neurons innervating the skin can release neuropeptides that are believed to modulate cellular proliferation, wound healing, pigmentation, and keratinocyte innate immune responses. While the ability of neuropeptides to stimulate keratinocyte production of inflammatory mediators has been demonstrated, there is no information concerning the mechanism(s) by which neuropeptide activation of keratinocyte cell surface receptors ultimately leads to the up-regulation of mediator production. In this study we used a keratinocyte cell line to identify the presence of substance P (SP) and calcitonin gene-related peptide (CGRP) receptors on keratinocytes and examined the effects of SP and CGRP stimulation on keratinocyte neuropeptide signaling, cell proliferation, and interleukin-1β (IL-1), interleukin-6 (IL-6), tumor necrosis factor α (TNF), and nerve growth factor (NGF) expression. Neuropeptide stimulation caused an up-regulation of neuropeptide receptor expression in keratinocytes and a dramatic increase in keratinocyte secretion of SP and CGRP, suggesting possible autocrine or paracrine stimulatory effects and amplification of neuropeptide signaling. Both SP and CGRP concentration-dependently stimulated cellular proliferation and the expression and secretion of inflammatory cytokines and NGF in keratinocytes. SP also activated all 3 families of mitogen activated protein kinases (MAPK) and nuclear factor κB (NFκB) in keratinocytes, while CGRP only activated p38 and extracellular signal related kinases1/2 (ERK1/2) MAPK. Neuropeptide stimulated inflammatory mediatory production in keratinocytes was reversed by ERK1/2 and JNK inhibitors. The current study is the first to observe; 1) that CGRP stimulates keratinocyte expression of CGRP and its receptor complex, 2) that SP and CGRP stimulate of IL-6 and TNF secretion in keratinocytes, 3) that SP activated all three MAPK families and the NFκB transcriptional signaling pathway in keratinocytes, and 4) that SP and CGRP stimulated inflammatory mediator production in keratinocytes is dependent on ERK1/2 and JNK activation. These studies provide evidence suggesting that disruption of ERK1/2 and JNK signaling may potentially be an effective therapy for inflammatory skin diseases and pain syndromes mediated by exaggerated sensory neuron-keratinocyte signaling.
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影响因子：
6.5
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