ΔNp63 controls a TLR3-mediated mechanism that abundantly provides thymic stromal lymphopoietin in atopic dermatitis.
ΔNp63 controls a TLR3-mediated mechanism that abundantly provides thymic stromal lymphopoietin in atopic dermatitis.
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DOI：
10.1371/journal.pone.0105498
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Ichimiya S
中科院分区：
文献类型：
--
作者：
Kubo T;Kamekura R;Kumagai A;Kawata K;Yamashita K;Mitsuhashi Y;Kojima T;Sugimoto K;Yoneta A;Sumikawa Y;Yamashita T;Sato N;Himi T;Ichimiya S
在特应性皮炎（AD）的皮肤病变中，角质形成细胞释放大量胸腺基质淋巴细胞生成素（TSLP），引起不利的炎症沿着皮肤损伤。然而，TSLP如何影响角质形成细胞本身仍然是未知的。在这项研究中，我们发现Δ Np 63，一个p53同源物，主要在角质形成细胞中表达，调节TSLP的受体复合物，决定了对自身来源的TSLP的易感性。采用免疫组织化学和定量RT-PCR方法检测皮肤组织和角质形成细胞中TSLP受体的表达，并在体外研究了Δ Np 63在TSLP受体表达中的功能相关性，以及在刺激感受细胞损伤的先天性受体的条件下，TSLP的自分泌和/或旁分泌途径的构成。结果表明，正常人上表皮角质形成细胞优先表达TSLP受体，而缺乏对TSLP受体表达有抑制作用的Δ Np 63。有趣的是，发现AD病变的表皮大量含有具有低水平或不可检测水平的Δ Np 63（Δ Np 63 lo/-）的角质形成细胞。此外，在缺乏Δ Np 63的情况下，角质形成细胞容易通过Toll样受体3（TLR 3）的刺激呈递TSLP和其他细胞因子。结合外源性TSLP本身增加角质形成细胞在没有Δ Np 63的情况下产生TSLP的证据，结果表明Δ Np 63 lo/-角质形成细胞在AD病变内TLR 3刺激后通过推定的自分泌和/或旁分泌途径产生TSLP，因为受损细胞和病原体的部分刺激TLR 3。
In the skin lesions of atopic dermatitis (AD), keratinocytes release large quantities of thymic stromal lymphopoietin (TSLP), causing unfavorable inflammation along with skin damage. Nevertheless, how TSLP influences keratinocytes themselves is still unknown. In this study, we showed that ΔNp63, a p53-homologue, predominantly expressed in keratinocytes regulated the receptor complex of TSLP, which determines susceptibility to self-derived TSLP. Expression of TSLP receptors in skin tissues and keratinocytes was assessed by immunohistochemistry and quantitative RT-PCR, and in vitro studies were also performed to examine the functional relevance of ΔNp63 in the expression of TSLP receptors and the constituting autocrine and/or paracrine pathway of TSLP under the condition of stimuli to innate receptors sensing cell damage. The results showed that normal keratinocytes in the upper epidermis preferentially expressed TSLP receptors and conversely lacked ΔNp63, which has an inhibitory effect on the expression of TSLP receptors. Interestingly, the epidermis of AD lesions was found to abundantly contain keratinocytes with low or undetectable levels of ΔNp63 (ΔNp63lo/-). Moreover, in the absence of ΔNp63, keratinocytes readily presented TSLP and other cytokines by stimuli through Toll-like receptor 3 (TLR3). Together with the evidence that extrinsic TSLP itself augments TSLP production by keratinocytes without ΔNp63, the results indicate that ΔNp63lo/- keratinocytes generate TSLP through a putative autocrine and/or paracrine pathway upon TLR3 stimulation within AD lesions, since moieties of damaged cells and pathogens stimulate TLR3.
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影响因子：
9
作者：
通讯作者：
--
DOI：
10.1084/jem.20062211
发表时间：
2007-02-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Allakhverdi Z;Comeau MR;Jessup HK;Yoon BR;Brewer A;Chartier S;Paquette N;Ziegler SF;Sarfati M;Delespesse G
通讯作者：
Delespesse G
影响因子：
14.2
作者：
De Benedetto, Anna;Rafaels, Nicholas M;McGirt, Laura Y;Ivanov, Andrei I;Georas, Steve N;Cheadle, Chris;Berger, Alan E;Zhang, Kunzhong;Vidyasagar, Sadasivan;Yoshida, Takeshi;Boguniewicz, Mark;Hata, Tissa;Schneider, Lynda C;Hanifin, Jon M;Gallo, Richard L;Novak, Natalija;Weidinger, Stephan;Beaty, Terri H;Leung, Donald Y M;Barnes, Kathleen C;Beck, Lisa A
通讯作者：
Beck, Lisa A
影响因子：
64.8
作者：
Mills, AA;Zheng, BH;Bradley, A
通讯作者：
Bradley, A
影响因子：
14.2
作者：
Brauweiler, Anne M.;Bin, Lianghua;Leung, Donald Y. M.
通讯作者：
Leung, Donald Y. M.