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

Autor: Kyu Han Kim, Bong Gun Ju, Hayan Jeong, Hyo Jin Chong, Yoon Sik Lee, Sunhyae Jang, Hyeri Jeong, Seok In Kim, Kwanghyun Lee, Su Jin Lee, Jee Youn Shin, Dong-Sik Shin, Young Eun Jeon
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Anti-Inflammatory Agents
Syk
IκB kinase
Proto-Oncogene Proteins c-fyn
NF-κB
lcsh:Chemistry
chemistry.chemical_compound
Mice
Gene expression
HaCaT Cells
SYK
lcsh:QH301-705.5
Spectroscopy
Skin
Mice
Inbred BALB C
atopic dermatitis
Chemistry
Kinase
TOR Serine-Threonine Kinases
NF-kappa B
General Medicine
Dipeptides
Computer Science Applications
Cell biology
I-kappa B Kinase
Molecular Docking Simulation
Female
skin atrophy
Protein Binding
Signal Transduction
Catalysis
Article
Dermatitis
Atopic
Inorganic Chemistry
FYN
Caffeic Acids
Fyn
Animals
Humans
Syk Kinase
Physical and Theoretical Chemistry
Molecular Biology
PI3K/AKT/mTOR pathway
CA-PH
Organic Chemistry
Amides
Disease Models
Animal
Gene Expression Regulation
lcsh:Biology (General)
lcsh:QD1-999
Cell culture
Dinitrofluorobenzene
Atrophy
Glycoconjugates
Transcription Factors
Zdroj: International Journal of Molecular Sciences, Vol 21, Iss 7160, p 7160 (2020)
International Journal of Molecular Sciences
Volume 21
Issue 19
ISSN: 1661-6596
1422-0067
Popis: 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.
Databáze: OpenAIRE
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