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Caffeoyl-Prolyl-Histidine Amide Inhibits Fyn and Alleviates Atopic Dermatitis-Like Phenotypes via Suppression of NF-?B Activation.

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-?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?B) signaling, which is required for nuclear factor kappa-light-chain-enhancer of activated B cells (NF-?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-?B activation, and Fyn may be a new therapeutic target of inflammatory skin diseases, such as AD.

SUBMITTER: Jeong H

PROVIDER: S-EPMC7582254 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Caffeoyl-Prolyl-Histidine Amide Inhibits Fyn and Alleviates Atopic Dermatitis-Like Phenotypes via Suppression of NF-κB Activation.

Jeong Hayan H Shin Jee Youn JY Lee Kwanghyun K Lee Su-Jin SJ Chong Hyo-Jin HJ Jeong Hyeri H Jeon Young-Eun YE Shin Dong-Sik DS Jang Sunhyae S Kim Kyu Han KH Kim Seok-In SI Lee Yoon-Sik YS Ju Bong-Gun BG

International journal of molecular sciences 20200928 19

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-P ...[more]

PMID: 32998341

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Project description:BackgroundJianpi Yangxue Qufeng Compound (JPYXQFC) is a Chinese medicine widely used in the clinical treatment of atopic dermatitis (AD) and has a significantly therapeutic effect. However, the mechanism of JPYXQFC in AD has been not understood clearly.ObjectiveThis study aimed to explore the effect of JPYXQFC on AD model cells and rats by regulating TLR4/MyD88/NF-κB signaling pathway.MethodsThe rats (n > 5) were given JPYXQFC decoction orally twice a day for three days, and their abdominal aortic blood was collected. HaCaT cell proliferation rate was tested by cell counting kit-8 (CCK-8) assays. We induced AD rat model through 2, 4-dinitrofluorobenzene (DNFB). AD rats were given oral JPYXQFC decoction and cetirizine (positive control). HaCaT cells were pretreated with JPYXQFC drug serum or cetirizine for 0.5 h and then stimulated with TNF-α/IFN-γ for 1 h. The mRNA levels of TLR4, MyD88, NF-κB, IL-4, IL-13, MCP1, TNF-α and TSLP were detected by quantitative real-time PCR (Q-RT-PCR), and TLR4/MyD88/NF-κB pathway protein expression was tested by Western blot. The total serum levels of immunoglobulin E (IgE), thymus and activation regulated chemokine/chemokine (C-C motif) ligand 17 (TARC/CCL17) were detected by enzyme-linked immunosorbent assay (ELISA). The epidermal thickness was detected by hematoxylin and eosin (HE) staining. The dermatitis area and score were measured by a ruler and a four-point scoring method, respectively.ResultsJPYXQFC significantly inhibited mRNA and protein expression of the TLR4/MyD88/NF-κB pathway and Histone H3 in TNF-α/IFN-γ-induced HaCaT cells and DNFB-induced rats, decreased the mRNA of IL-4, IL-13, MCP1, CCL22, TSLP and the level of AD-related genes IgE and TAEC/CCL17 of TNF-α/IFN-γ-induced HaCaT cells. Meanwhile, JPYXQFC significantly reduced the dermatitis area and dermatitis score in DNFB-induced rats, inhibited the levels of pro-inflammatory cytokines IL-6 and TNF-α, and upregulated FLG, as well as inhibited the levels of IgE and TARC/CCL17 in the serum of AD rats.ConclusionJPYXQFC alleviates AD by inhibiting the activation of TLR4/MyD88/NF-κB pathway.

Dataset Information

Caffeoyl-Prolyl-Histidine Amide Inhibits Fyn and Alleviates Atopic Dermatitis-Like Phenotypes via Suppression of NF-?B Activation.

Publications

Caffeoyl-Prolyl-Histidine Amide Inhibits Fyn and Alleviates Atopic Dermatitis-Like Phenotypes via Suppression of NF-κB Activation.

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