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.
Highlights
Caffeic acid (CA; 3,4-dihydroxycinnamic acid), which is a phenolic compound produced from a variety of plants, removes reactive oxygen species (ROS) by delocalization of the unpaired electron in the extended conjugated side chain [1,2]
We further examined the expression of cytokines related to atopic dermatitis (AD)
We further investigated the molecular mechanism of caffeoyl-prolyl-histidine amide (CA-PH)-mediated alleviation of AD-like phenotypes using cell line and mouse models
Summary
Caffeic acid (CA; 3,4-dihydroxycinnamic acid), which is a phenolic compound produced from a variety of plants, removes reactive oxygen species (ROS) by delocalization of the unpaired electron in the extended conjugated side chain [1,2]. CA, which is a major compound of water extract from Ixeris dentata, decreased expression of chemokines including IL-8 and TARC in keratinocytes and suppressed NF-κB activation through inhibition of p38 phosphorylation, resulting in reduction of the level of IL-8 and TNFα in mast cells [7]. Fyn transmits signals from diverse cell surface receptors to cytoplasmic signal transduction cascades [13] It plays important roles in the regulation of diverse biological functions, such as apoptosis, survival, adhesion, migration, neuronal transmission, and immunity [14,15,16,17]. Inhibition of Fyn suppresses production and secretion of pro-inflammatory cytokines and IgE in 1-fluoro-2,4-dinitrobenzene (DNFB)-induced allergic dermatitis models, as well as inhibition of mast cell degranulation [31].
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