title: Transforming growth factor-β1 mediates psoriasis-like lesions via a Smad3-dependent mechanism in mice.
abstract: 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.
authors.affiliation: Li Ka Shing Institute of Health Sciences and Department of Medicine and Therapeutics, The Chinese University of HongKong, Hong Kong, China; School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Meng
authors.forename: Xiao-Ru
authors.initials: XR
authors.lastname: Huang
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Wang
authors.forename: Liu
authors.initials: L
authors.lastname: Yang
authors.forename: Hui Yao
authors.initials: HY
authors.lastname: Lan
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D020381:Interleukin-17 / Q000097:blood; D053759:Interleukin-23 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D007546:Isoquinolines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008822:Mice, Transgenic; D009824:Ointments; D011565:Psoriasis / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D012867:Skin / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D051900:Smad3 Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: C508504:6,7-dimethyl-2-(2E)-3-(1-methyl-2-phenyl-1H-pyrrolo(2,3-b)pyridin-3-yl-prop-2-enoyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride; D020381:Interleukin-17; D053759:Interleukin-23; D015850:Interleukin-6; D007546:Isoquinolines; D009824:Ointments; D011725:Pyridines; D011758:Pyrroles; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D053773:Transforming Growth Factor beta1; C577686:interleukin-6, mouse
keywords: Smad3 inhibitor; Th17 cells; psoriasis; transforming growth factor-β signalling