JOURNAL ARTICLE

Transforming growth factor-β1 mediates psoriasis-like lesions via a Smad3-dependent mechanism in mice

Yun Zhang, Xiao-Ming Meng, Xiao-Ru Huang, Xiao-Jing Wang, Liu Yang, Hui Yao Lan
Clinical and Experimental Pharmacology & Physiology 2014, 41 (11): 921-32
25132073
Transforming growth factor (TGF)-β1 signals through downstream Smad-dependent and -independent pathways to exert its biological actions. It has been reported that overexpression of TGF-β1 results in the development of psoriasis-like lesions in a mouse model of K5.TGF-β(WT) transgenic mice. However, the signalling mechanisms by which TGF-β1 mediates the development of psoriasis-like lesions remain unknown. The aim of the present study was to investigate the hypothesis that TGF-β1 mediates the development of psoriasis-like lesions via a Smad3-dependent mechanism. This was tested in a mouse model of K5.TGF-β(WT) transgenic mice by blocking TGF-β signalling with a specific Smad3 inhibitor. Topical treatment with a Smad3 inhibitor markedly blocked TGF-β/Smad3 signalling and progressive psoriasis-like lesions in K5.TGF-β(WT) transgenic mice, as evidenced by decreased skin severity scores, double skin fold thickness (DSFT) scores, infiltration of CD3(+) T cells and F4/80(+) macrophages and the degree of fibrosis in the dermis. This was associated with a marked reduction in TGF-β1, interleukin (IL)-6, IL-23 and IL-17A both locally in skin plaque lesions and systemically in the plasma, resulting in inhibition of both the T helper (Th) 17 cell transcription factor RORγt and accumulation of CD4(+) IL-17A(+) cells within the skin plaque lesions. In conclusion, TGF-β1 mediates the development of psoriasis-like lesions via a Smad3-dependent, Th17-mediated mechanism. Targeting TGF-β/Smad3 signalling with a Smad3 inhibitor may represent a novel and effective therapy for psoriasis.

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