期刊
FASEB JOURNAL
卷 37, 期 10, 页码 -出版社
WILEY
DOI: 10.1096/fj.202200951RRR
关键词
anti-inflammatory; atopic dermatitis; NF-& kappa;B signaling; PYR-41; ubiquitin
The study investigated the therapeutic effects of PYR-41 on atopic dermatitis. The results showed that PYR-41 can activate the NF-?B signaling pathway by reducing the ubiquitination levels of specific molecules and inhibiting the degradation of I?Ba. In addition, in a mouse model, PYR-41 treatment significantly improved symptoms and reduced the expression of inflammatory markers.
PYR-41 is an irreversible and cell permeable inhibitor of ubiquitin-activating enzyme E1, and has been reported to inhibit the degradation of I?B protein. Previous studies have shown that PYR-41 has effects on anti-inflammatory, but whether it has therapeutic effects on allergic dermatitis is unclear. The aim of this research was to explore the therapeutic effects of PYR-41 on atopic dermatitis. The effects of PYR-41 on the activation of NF-?B signaling pathway and the expression of inflammatory genes in HaCat cells were tested by western blot and qPCR. A mouse model was built, and the AD-like skin lesions were induced by 2,4-dinitrochlorobenzene (DNCB). Then, the treatment effects of PYR-41 were examined by skin severity score, ear swelling, ELISA, and qPCR. The results showed that PYR-41 can significantly reduce the K63-linked ubiquitination level of nuclear factor-?B essential modulator (NEMO) and tumor necrosis factor receptor associated factor 6 (TRAF6), inhibit the proteasomal degradation of I?Ba, thereby activate TNF-a-induced NF-?B signaling pathway in HaCat cells. In addition, DNCB-treated mice have significant reduction in symptoms after treated by PYR-41, including reduced ear thickening and reduced skin damage. Serum tests showed that PYR-41 significantly reduced the expression of IgE, IFN-?, and TNF-a. In conclusion, the current results suggest that PYR-41 has potential to reduce the symptoms of atopic dermatitis.
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