International journal of molecular sciences, 2020-09, Vol.21 (19), p.7160
2020
Details
- Autor(en) / Beteiligte
- Titel
- Caffeoyl-Prolyl-Histidine Amide Inhibits Fyn and Alleviates Atopic Dermatitis-Like Phenotypes via Suppression of NF-κB Activation
- Ist Teil von
- International journal of molecular sciences, 2020-09, Vol.21 (19), p.7160
- Ort / Verlag
- Switzerland: MDPI AG
- Erscheinungsjahr
- 2020
- Link zum Volltext
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1422-0067, 1661-6596eISSN: 1422-0067DOI: 10.3390/ijms21197160Titel-ID: cdi_doaj_primary_oai_doaj_org_article_14291619b3e344eaade0fd89f6997085
- Format
- –
- Schlagworte
- Adenosine triphosphate, Amides - chemistry, Animal models, Animals, Anti-Inflammatory Agents - chemical synthesis, Anti-Inflammatory Agents - metabolism, Anti-Inflammatory Agents - pharmacology, Atopic dermatitis, Atrophy, Atrophy - chemically induced, Atrophy - drug therapy, Atrophy - genetics, Atrophy - pathology, Binding sites, Biological activity, CA-PH, Caffeic acid, Caffeic Acids - chemistry, Caffeic Acids - pharmacology, Cell activation, Cytokines, Deoxyribonucleic acid, Dermatitis, Dermatitis, Atopic - chemically induced, Dermatitis, Atopic - drug therapy, Dermatitis, Atopic - genetics, Dermatitis, Atopic - pathology, Dinitrofluorobenzene - administration & dosage, Dipeptides - chemistry, Disease Models, Animal, DNA, DNA damage, Eczema, Enzyme inhibitors, Enzymes, Female, Fyn, Fyn protein, Gene expression, Gene Expression Regulation, Glucocorticoids, Glycoconjugates - chemical synthesis, Glycoconjugates - metabolism, Glycoconjugates - pharmacology, HaCaT Cells, Histidine, Humans, Hydrogen bonds, I-kappa B Kinase - genetics, I-kappa B Kinase - metabolism, IKK protein, Inflammation, Kinases, Lymphocytes B, Mast cells, Mice, Mice, Inbred BALB C, Molecular docking, Molecular Docking Simulation, NF-kappa B - antagonists & inhibitors, NF-kappa B - genetics, NF-kappa B - metabolism, NF-κB, NF-κB protein, Nuclear transport, Pathogenesis, Phenotypes, Phosphorylation, Proline, Protein Binding, Protein-tyrosine kinase, Proto-Oncogene Proteins c-fyn - antagonists & inhibitors, Proto-Oncogene Proteins c-fyn - chemistry, Proto-Oncogene Proteins c-fyn - genetics, Proto-Oncogene Proteins c-fyn - metabolism, Rapamycin, Signal Transduction, Signaling, Skin - drug effects, Skin - metabolism, Skin - pathology, skin atrophy, Skin diseases, Spleen, SYK, Syk Kinase - genetics, Syk Kinase - metabolism, Syk protein, Therapeutic targets, Thickening, TOR protein, TOR Serine-Threonine Kinases - genetics, TOR Serine-Threonine Kinases - metabolism, Transcription Factors - genetics, Transcription Factors - metabolism, Tyrosine