The NF-κB, p38 MAPK and STAT1 pathways differentially regulate the dsRNA-mediated innate immune responses of epidermal keratinocytes
The NF-κB, p38 MAPK and STAT1 pathways differentially regulate the dsRNA-mediated innate immune responses of epidermal keratinocytes
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DOI：
10.1093/intimm/dxn048
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发表时间：
2008-07-01
影响因子：
4.4
通讯作者：
Hashimoto, Koji
中科院分区：
文献类型：
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作者：
Dai, Xiuju;Sayama, Koji;Hashimoto, Koji
表皮是人体与环境之间的主要边界，也是抵御微生物病原体的第一道防线。趋化因子和细胞因子的产生是启动先天免疫应答病毒感染的重要步骤。表皮角质形成细胞产生ifn - α， - β和巨噬细胞炎症蛋白(MIP)-1 α响应双链RNA （dsRNA）或病毒感染。我们发现，人角质形成细胞产生细胞因子[肿瘤坏死因子(TNF)- α， IL-1 β和IL-15]和趋化因子[MIP-1 β， RANTES和肝脏和激活调节趋化因子（LARC）]响应dsRNA，激活核因子κ B (nf - κ B)， p38丝裂原活化蛋白激酶（MAPK）和信号转导和转录激活因子1 （STAT1）途径。为了研究这些途径在其产生中的作用，我们用腺病毒载体（Ax）转染角质形成细胞，该载体携带一种显性阴性形式的抑制剂kappa B α (I kappa B α) (I kappa B α M)，一种显性阴性突变形式的STAT1 （STAT1F）或细胞因子信号传导1的抑制因子（SOCS1）。转染AxI kappa B α M或添加p38抑制剂（SB203580）可显著降低dsrna介导的tnf - α、IL-1 β和MIP-1 α的产生，但不影响ifn - β、IL-15、MIP-1 β、RANTES或LARC的产生。转染AxSTAT1F或AxSOCS1可抑制dsrna介导的tnf - α、IL-15、MIP-1 α、MIP-1 β、RANTES和LARC的产生，但对ifn - β或IL-1 β无抑制作用。综上所述，NF-kappa B、p38 MAPK和STAT1通路在表皮角质形成细胞中调控dsrna介导的先天免疫反应存在差异。
The epidermis is the primary boundary between the body and the environment, and it serves as the first line of defense against microbial pathogens. Production of chemokines and cytokines is an important step in the initiation of innate immune responses to viral infections. Epidermal keratinocytes produce IFN-alpha, -beta and macrophage inflammatory protein (MIP)-1 alpha in response to double-stranded RNA (dsRNA) or viral infections. We showed that human keratinocytes produced cytokines [tumor necrosis factor (TNF)-alpha, IL-1 beta and IL-15] and chemokines [MIP-1 beta, RANTES and liver and activation-regulated chemokine (LARC)] in response to dsRNA, with activation of the nuclear factor kappa B (NF-kappa B), p38 mitogen-activated protein kinase (MAPK) and signal transducers and activators of transcription 1 (STAT1) pathways. To study the roles of these pathways in their production, we transfected keratinocytes with adenoviral vectors (Ax) carrying a dominant-negative form of inhibitor kappa B alpha (I kappa B alpha) (I kappa B alpha M), a dominant-negative mutant form of STAT1 (STAT1F) or suppressors of cytokine signaling 1 (SOCS1). Transfection with AxI kappa B alpha M or addition of a p38 inhibitor (SB203580) significantly decreased the dsRNA-mediated production of TNF-alpha, IL-1 beta and MIP-1 alpha, but not of IFN-beta, IL-15, MIP-1 beta, RANTES or LARC. Transfection with AxSTAT1F or AxSOCS1 inhibited the dsRNA-mediated production of TNF-alpha, IL-15, MIP-1 alpha, MIP-1 beta, RANTES and LARC, but not IFN-beta or IL-1 beta. In conclusion, the NF-kappa B, p38 MAPK and STAT1 pathways differentially regulate dsRNA-mediated innate immune responses in epidermal keratinocytes.