PYR‐41, an inhibitor of ubiquitin‐activating enzyme E1, attenuates 2,4‐dinitrochlorobenzene‐induced atopic dermatitis‐like skin lesions in mice

Abstract

AbstractPYR‐41 is an irreversible and cell permeable inhibitor of ubiquitin‐activating enzyme E1, and has been reported to inhibit the degradation of IκB 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‐κB 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‐κB essential modulator (NEMO) and tumor necrosis factor receptor associated factor 6 (TRAF6), inhibit the proteasomal degradation of IκBα, thereby activate TNF‐α‐induced NF‐κB 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‐γ, and TNF‐α. In conclusion, the current results suggest that PYR‐41 has potential to reduce the symptoms of atopic dermatitis.