Increased βTrCP are associated with imiquimod-induced psoriasis-like skin inflammation in mice via NF-κB signaling pathway

Ruilian Li, Juan Wang, Xin Wang, Jun Zhou, Mei Wang, Huiqun Ma, Shengxiang Xiao
Gene 2016 October 30, 592 (1): 164-171
Psoriasis is a common inflammatory skin disease characterized by T cell-mediated hyperproliferation of keratinocytes, increased angiogenesis and inflammation. Accumulating evidence suggests that some keratinocyte differentiation events are controlled by the ubiquitin/proteasome system. β-transducin repeat-containing protein (βTrCP) serve as substrate recognition component of E3 ubiquitin ligases that control stability of important regulators of signal transduction including the nuclear factor (NF)-κB signaling, a key regulatory element in inflammatory pathways related to psoriasis, suggesting a potential role of βTrCP in psoriasis pathogenesis. However, no published study has investigated the role of βTrCP in the etiology of psoriasis. Here, we combined an in vitro cell model of tumor necrosis factor (TNF)-α-induced keratinocyte inflammation and an animal model of imiquimod (IMQ)-induced psoriasis-like inflammation to investigate the pathogenic mechanisms in psoriasis-like dermatitis and assess its βTrCP/NF-κB dependency. Daily application of IMQ on mouse back skin induced inflamed scaly skin lesions resembling plaque type psoriasis. These lesions were associated with elevated βTrCP levels, reduced inhibitor κB (IκB), and enhanced NF-κB activation in epidermal tissues. Furthermore, βTrCP knockdown via siRNA in in TNF-α-stimulated HaCaT and normal human epidermal keratinocytes (NHEK) cells significantly inhibited the over-activation of NF-κB and expression of intercellular adhesion molecule 1 (ICAM-1), demonstrating a pivotal role of βTrCP in regulation the TNF-α-activated NF-κB inflammatory pathways. Moreover, downregulation of βTrCP through lentiviral shRNA ameliorates IMQ-induced psoriasis-like skin lesions in vivo. In conclusion, βTrCP is involved in the NF-κB signaling mediated-, psoriasis-related inflammation and represent a novel target for developing agents to treat psoriasis.

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