Ann Dermatol.  2019 Dec;31(6):631-639. 10.5021/ad.2019.31.6.631.

Selective Inhibition of β-Catenin/Co-Activator Cyclic AMP Response Element-Binding Protein-Dependent Signaling Prevents the Emergence of Hapten-Induced Atopic Dermatitis-Like Dermatitis

• Matsuda-Hirose H
• Yamate T
• Goto M
• Katoh A
• Kouji H
• Yamamoto Y
• Sakai T
• Uemura N
• Kobayashi
• Hatano Y

• KMID: 2461985
• DOI: http://doi.org/10.5021/ad.2019.31.6.631

Abstract

BACKGROUND
The canonical Wnt/β-catenin signaling pathway is a fundamental regulatory system involved in various biological events. ICG-001 selectively blocks the interaction of β-catenin with its transcriptional co-activator cyclic AMP response element-binding protein (CBP). Recent studies have provided convincing evidence of the inhibitory effects of ICG-001 on Wnt-driven disease models, such as organ fibrosis, cancer, acute lymphoblastic leukemia, and asthma. However, the effects of ICG-001 in atopic dermatitis (AD) have not been investigated.
OBJECTIVE
To investigate whether β-catenin/CBP-dependent signaling was contributed in the pathogenesis of AD and ICG-001 could be a therapeutic agent for AD.
METHODS
We examined the effects of ICG-001 in an AD-like murine model generated by repeated topical application of the hapten, oxazolone (Ox). ICG-001 or vehicle alone was injected intraperitoneally every day during the development of AD-like dermatitis arising from once-daily Ox treatment.
RESULTS
Ox-induced AD-like dermatitis characterized by increases in transepidermal water loss, epidermal thickness, dermal thickness accompanied by increased myofibroblast and mast cell counts, and serum levels of thymic stromal lymphopoietin and thymus and activation-regulated chemokine, and decreases in stratum corneum hydration, were virtually normalized by the treatment with ICG-001. Elevated serum levels of periostin tended to be downregulated, without statistical significance.
CONCLUSION
These results suggest that β-catenin/CBP-dependent signaling might be involved in the pathogenesis of AD and could be a therapeutic target.

Keyword

Atopic dermatitis; Mouse; Therapy

MeSH Terms

Animals
Asthma
Chemokine CCL17
Cyclic AMP Response Element-Binding Protein
Cyclic AMP*
Dermatitis*
Dermatitis, Atopic
Fibrosis
Mast Cells
Mice
Myofibroblasts
Oxazolone
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Water
Chemokine CCL17
Cyclic AMP
Cyclic AMP Response Element-Binding Protein
Oxazolone
Water

Figure

• 

  Fig. 1 Effect of ICG-001 in an atopic dermatitis (AD)-like model induced by repeated oxazolone (Ox) treatments. As Ox treatments proceeded, the gross appearances of AD lesions showing remarkable erythema, lichenification, and pronounced scales compared with the non-treated control group (normal). ICG-001 treatment (Ox+ICG-001) remarkably attenuated AD-like skin lesions compared with vehicle only mice (Ox+vehicle).

• 

  Fig. 2 Effects of ICG-001 on epidermal hyperplasia, dermal fibrosis, and inflammatory cell infiltration in atopic dermatitis (AD)-like skin. (A) H&E stained sections are shown at 100x magnification. (B, C) Skin thickening as determined by H&E staining. ICG-001 suppressed epidermal hyperplasia and dermal fibrosis induced by repeated oxazolone (Ox) treatment. (D, E) α-Smooth muscle actin (SMA) positive myofibroblasts by immunohistochemical staining and mast cells by Giemsa-staining per high power field. **p<0.01. ICG-001 significantly suppressed myofibroblast proliferation and mast cell infiltration in the dermis. Control group (normal) (n=4), Vehicle only mice (Ox+vehicle) (n=8), ICG-001 treatment (Ox+ICG-001) (n=8). *0.05>p>0.01, **p<0.01.

• 

  Fig. 3 Effect of ICG-001 on epidermal permeability barrier function in atopic dermatitis (AD)-like skin. ICG-001 treated mice (oxazolone [Ox]+ICG-001) showed lower basal transepidermal water loss (TEWL) (A) and higher stratum corneum (SC) hydration (B) compared with vehicle only mice (Ox+vehicle). Control group (normal) (n=4), Vehicle only mice (Ox+vehicle) (n=8), ICG-001 treatment (Ox+ICG-001) (n=8). *0.05>p>0.01, **p<0.01.

• 

  Fig. 4 Effect of ICG-001 on the serum levels of immunoglobulin E (IgE), thymic stromal lymphopoietin (TSLP), thymus and activation-regulated chemokine (TARC), and periostin. ICG-001 treatment of atopic dermatitis (AD) mice suppressed serum TSLP and TARC levels (B, C), and tended to suppress serum IgE and periostin levels, without significance (A, D). Control group (normal) (n=4), Vehicle only mice (oxazolone [Ox]+vehicle) (n=8), ICG-001 treatment (Ox+ICG-001) (n=8). *0.05>p>0.01, **p<0.01.

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