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 = 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

다국어 초록 (Multilingual 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. (Ann Dermatol 31(6) 631∼639, 2019)

참고문헌 (Reference)

1 Clevers H, "Wnt/β-catenin signaling and disease" 149 : 1192-1205, 2012

2 Nishikawa K, "Wnt/β-Catenin Signaling as a potential target for the treatment of liver cirrhosis using antifibrotic drugs" 19 : E3103-, 2018

3 Gattinoni L, "Wnt/beta-catenin signaling in T-cell immunity and cancer immunotherapy" 16 : 4695-4701, 2010

4 Hatano Y, "The Th2 cytokine, interleukin-4, abrogates the cohesion of normal stratum corneum in mice : implications for pathogenesis of atopic dermatitis" 22 : 30-35, 2013

5 Krishnamurthy N, "Targeting the Wnt/beta-catenin pathway in cancer : update on effectors and inhibitors" 62 : 50-60, 2018

6 Takahashi-Yanaga F, "Targeting Wnt signaling : can we safely eradicate cancer stem cells" 16 : 3153-3162, 2010

7 Gang EJ, "Small-molecule inhibition of CBP/catenin interactions eliminates drug-resistant clones in acute lymphoblastic leukemia" 33 : 2169-2178, 2014

8 Koopmans T, "Selective targeting of CREB-binding protein/β-catenin inhibits growth of and extracellular matrix remodelling by airway smooth muscle" 173 : 3327-3341, 2016

9 Yamaguchi Y, "Periostin in skin tissue and skin-related diseases" 63 : 161-170, 2014

10 Kabashima K, "New concept of the pathogenesis of atopic dermatitis : interplay among the barrier, allergy, and pruritus as a trinity" 70 : 3-11, 2013

11 Hatano Y, "Murine atopic dermatitis responds to peroxisome proliferator-activated receptors alpha and beta/delta(but not gamma)and liver X receptor activators" 125 : 160-169, 2010

12 Blauvelt A, "Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids(LIBERTY AD CHRONOS) : a 1-year, randomised, double-blinded, placebo-controlled, phase 3 trial" 389 : 2287-2303, 2017

13 Akcora BÖ, "Inhibition of canonical WNT signaling pathway by β-catenin/CBP inhibitor ICG-001ameliorates liver fibrosis in vivo through suppression of stromal CXCL12" 1864 : 804-818, 2018

14 Kinoshita H, "Cytokine milieu modulates release of thymic stromal lymphopoietin from human keratinocytes stimulated with double-stranded RNA" 123 : 179-186, 2009

15 Man MQ, "Characterization of a hapten-induced, murine model with multiple features of atopic dermatitis : structural, immunologic, and biochemical changes following single versus multiple oxazolone challenges" 128 : 79-86, 2008

16 Beyer C, "Blockade of canonical Wnt signalling ameliorates experimental dermal fibrosis" 72 : 1255-1258, 2013

17 Wei Zhang, "Betamethasone Butyrate Propionate Inhibits the Induction of Thymic Stromal Lymphopoietin in Cultured Normal Human Keratinocytes" 대한피부과학회 28 (28): 772-775, 2016

18 Elias PM, "Basis for the barrier abnormality in atopic dermatitis : outside-inside-outside pathogenic mechanisms" 121 : 1337-1343, 2008

19 Leung DY, "Atopic dermatitis : the skin as a window into the pathogenesis of chronic allergic diseases" 96 : 302-318, 1995

20 Gaddis M, "Altering cancer transcriptomes using epigenomic inhibitors" 8 : 9-, 2015

21 Emami KH, "A small molecule inhibitor of beta-catenin/CREBbinding protein transcription [corrected]" 101 : 12682-12687, 2004