start-ver=1.4
cd-journal=joma
no-vol=73
cd-vols=
no-issue=2
article-no=
start-page=323
end-page=331
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2024
dt-pub=202404
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Topical application of activator protein-1 inhibitor T-5224 suppresses inflammation and improves skin barrier function in a murine atopic dermatitis-like dermatitis
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=Background: Selective activator protein (AP)-1 inhibitors are potentially promising therapeutic agents for atopic dermatitis (AD) because AP-1 is an important regulator of skin inflammation. However, few studies have investigated the effect of topical application of AP-1 inhibitors in treating inflammatory skin disorders. <br>
Methods: Immunohistochemistry was conducted to detect phosphorylated AP-1/c-Jun expression of skin lesions in AD patients. In the in vivo study, 1 % T-5224 ointment was topically applied for 8 days to the ears of 2,4 dinitrofluorobenzene challenged AD-like dermatitis model mice. Baricitinib, a conventional therapeutic agent Janus kinase (JAK) inhibitor, was also topically applied. In the in vitro study, human epidermal keratinocytes were treated with T-5224 and stimulated with AD-related cytokines. <br>
Results: AP-1/c-Jun was phosphorylated at skin lesions in AD patients. In vivo, topical T-5224 application inhibited ear swelling (P < 0.001), restored filaggrin (Flg) expression (P < 0.01), and generally suppressed immune-related pathways. T-5224 significantly suppressed Il17a and l17f expression, whereas baricitinib did not.Baricitinib suppressed Il4, Il19, Il33 and Ifnb expression, whereas T-5224 did not. Il1a, Il1b, Il23a, Ifna, S100a8, and S100a9 expression was cooperatively downregulated following the combined use of T5224 and baricitinib. In vitro, T-5224 restored the expression of FLG and loricrin (LOR) (P < 0.05) and suppressed IL33 expression (P < 0.05) without affecting cell viability and cytotoxicity. <br>
Conclusions: Topical T-5224 ameliorates clinical manifestations of AD-like dermatitis in mice. The effect of this inhibitor is amplified via combined use with JAK inhibitors.
en-copyright=
kn-copyright=

en-aut-name=SasakuraMinori
en-aut-sei=Sasakura
en-aut-mei=Minori
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=UrakamiHitoshi
en-aut-sei=Urakami
en-aut-mei=Hitoshi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=TachibanaKota
en-aut-sei=Tachibana
en-aut-mei=Kota
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=IkedaKenta
en-aut-sei=Ikeda
en-aut-mei=Kenta
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=HasuiKen-Ichi
en-aut-sei=Hasui
en-aut-mei=Ken-Ichi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=MatsudaYoshihiro
en-aut-sei=Matsuda
en-aut-mei=Yoshihiro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=SunagawaKo
en-aut-sei=Sunagawa
en-aut-mei=Ko
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

en-aut-name=EnnishiDaisuke
en-aut-sei=Ennishi
en-aut-mei=Daisuke
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=8
ORCID=

en-aut-name=TomidaShuta
en-aut-sei=Tomida
en-aut-mei=Shuta
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=9
ORCID=

en-aut-name=MorizaneShin
en-aut-sei=Morizane
en-aut-mei=Shin
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=10
ORCID=

affil-num=1
en-affil=Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
kn-affil=

affil-num=2
en-affil=Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
kn-affil=

affil-num=3
en-affil=Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
kn-affil=

affil-num=4
en-affil=Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
kn-affil=

affil-num=5
en-affil=Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
kn-affil=

affil-num=6
en-affil=Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
kn-affil=

affil-num=7
en-affil=Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
kn-affil=

affil-num=8
en-affil=Center for Comprehensive Genomic Medicine, Okayama University Hospital
kn-affil=

affil-num=9
en-affil=Center for Comprehensive Genomic Medicine, Okayama University Hospital
kn-affil=

affil-num=10
en-affil=Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
kn-affil=
en-keyword=AP-1 inhibitor
kn-keyword=AP-1 inhibitor
en-keyword=Atopic dermatitis
kn-keyword=Atopic dermatitis
en-keyword=Baricitinib
kn-keyword=Baricitinib
en-keyword=T-5224
kn-keyword=T-5224
en-keyword=Topical application
kn-keyword=Topical application
END