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- Title
Caffeoyl-Prolyl-Histidine Amide Inhibits Fyn and Alleviates Atopic Dermatitis-Like Phenotypes via Suppression of NF-κB Activation.
- Authors
Jeong, Hayan; Shin, Jee Youn; Lee, Kwanghyun; Lee, Su-Jin; Chong, Hyo-Jin; Jeong, Hyeri; Jeon, Young-Eun; Shin, Dong-Sik; Jang, Sunhyae; Kim, Kyu Han; Kim, Seok-In; Lee, Yoon-Sik; Ju, Bong-Gun
- Abstract
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-κB. 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 (IκB) signaling, which is required for nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) 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-κB activation, and Fyn may be a new therapeutic target of inflammatory skin diseases, such as AD.
- Subjects
NF-kappa B; RAPAMYCIN; AMYLOID beta-protein precursor; PHENOTYPES; SKIN inflammation; CAFFEIC acid; ATOPIC dermatitis
- Publication
International Journal of Molecular Sciences, 2020, Vol 21, Issue 19, p7160
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms21197160