期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 21, 期 19, 页码 -出版社
MDPI
DOI: 10.3390/ijms21197160
关键词
atopic dermatitis; CA-PH; Fyn; NF-κ B; SYK; skin atrophy
资金
- Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Education [2018R1D1A1B07045909]
- Industrial Strategic Technology Development Program of the Ministry of Trade, Industry, and Energy (MOTIE) [10077652]
- Korean Evaluation Institute of Industrial Technology (KEIT)
- Korea Evaluation Institute of Industrial Technology (KEIT) [10077652] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
- National Research Foundation of Korea [2018R1D1A1B07045909] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Caffeic acid (CA) is produced from a variety of plants and has diverse biological functions, including anti-inflammation activity. It has been recently demonstrated that caffeoyl-prolyl-histidine amide (CA-PH), which is CA conjugated with proline-histidine dipeptide, relieves atopic dermatitis (AD)-like phenotypes in mouse. In this study, we investigated the molecular mechanism underlying CA-PH-mediated alleviation of AD-like phenotypes using cell line and AD mouse models. We confirmed that CA-PH suppresses AD-like phenotypes, such as increased epidermal thickening, infiltration of mast cells, and dysregulated gene expression of cytokines. CA-PH suppressed up-regulation of cytokine expression through inhibition of nuclear translocation of NF-kappa B. Using a CA-PH affinity pull-down assay, we found that CA-PH binds to Fyn. In silico molecular docking and enzyme kinetic studies revealed that CA-PH binds to the ATP binding site and inhibits Fyn competitively with ATP. CA-PH further suppressed spleen tyrosine kinase (SYK)/inhibitor of nuclear factor kappa B kinase (IKK)/inhibitor of nuclear factor kappa B (I kappa B) signaling, which is required for nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) activation. In addition, chronic application of CA-PH, in contrast with that of glucocorticoids, did not induce up-regulation of regulated in development and DNA damage response 1 (REDD1), reduction of mammalian target of rapamycin (mTOR) signaling, or skin atrophy. Thus, our study suggests that CA-PH treatment may help to reduce skin inflammation via down-regulation of NF-kappa B activation, and Fyn may be a new therapeutic target of inflammatory skin diseases, such as AD.
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