The Janus kinase inhibitor JTE-052 improves skin barrier function through suppressing signal transducer and activator of transcription 3 signaling

Amano, Wataru; Nakajima, Saeko; Kunugi, Hayato; Numata, Yasuharu; Kitoh, Akihiko; Egawa, Gyohei; Dainichi, Teruki; Honda, Tetsuya; Otsuka, Atsushi; Kimoto, Yukari; Yamamoto, Yasuo; Tanimoto, Atsuo; Matsushita, Mutsuyoshi; Miyachi, Yoshiki; Kabashima, Kenji

doi:10.1016/j.jaci.2015.03.051

Cited by 200 publications

(194 citation statements)

References 56 publications

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“…Th2 cytokines downregulate the expression of the major EDC genes, including FLG, LOR and involucrin [121,122,123,124], independent of the FLG genotype [125], and suppress keratinocyte differentiation via STAT3. Topical treatment with the Janus kinase (JAK) inhibitor downregulated STAT3 activation and restored skin barrier function by inducing terminal differentiation in AD animal models [126]. Topical and oral JAK inhibitors, such as tofacitinib, baricitinib and PF-04965842, are in phase II trials for AD [79].…”

Section: Immunological Abnormalitiesmentioning

confidence: 99%

Molecular Mechanisms of Cutaneous Inflammatory Disorder: Atopic Dermatitis

Kim

Cho

et al. 2016

IJMS

103

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Atopic dermatitis (AD) is a multifactorial inflammatory skin disease resulting from interactions between genetic susceptibility and environmental factors. The pathogenesis of AD is poorly understood, and the treatment of recalcitrant AD is still challenging. There is accumulating evidence for new gene polymorphisms related to the epidermal barrier function and innate and adaptive immunity in patients with AD. Newly-found T cells and dendritic cell subsets, cytokines, chemokines and signaling pathways have extended our understanding of the molecular pathomechanism underlying AD. Genetic changes caused by environmental factors have been shown to contribute to the pathogenesis of AD. We herein present a review of the genetics, epigenetics, barrier dysfunction and immunological abnormalities in AD with a focus on updated molecular biology.

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Section: Immunological Abnormalitiesmentioning

confidence: 99%

Molecular Mechanisms of Cutaneous Inflammatory Disorder: Atopic Dermatitis

Kim

Cho

et al. 2016

IJMS

103

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“…TSLP signaling was also reported to recall the memory of Th2 response in established mouse model of AD [42]. Furthermore, TSLP was found to downregulate filaggrin expression via activating the janus kinase-STAT3 pathway that influenced the skin barrier function [24,43]. The TSLP isoform (short/long) ratio is altered in several inflammatory disorders, which has implications for the treatment and prevention of AD [44].…”

Section: Epidermal Tslp: a Factor Link Two Major Pathogenesis In Admentioning

confidence: 98%

Potential Treatments for Atopic Dermatitis

Kao¹,

Shieh²,

Lee³

et al. 2016

J immuno Biol

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Atopic Dermatitis (AD) is the most common pruritic inflammatory skin disease which causes economic and social burden. AD is not curable and therapeutic options are limited. Currently, the therapeutic approaches to AD include topical treatment, phototherapy, and systemic treatment. Although traditional therapeutic strategies are efficacious in ameliorating the symptoms of AD in most patients, sometimes it is a tough challenge for physicians as AD is catastrophic and difficult to treat. Several potential treatments for AD are being studied owing to a clearer understanding of its pathogenesis. Additionally, animal models of AD allow comprehensive and thorough investigation of pathogenesis and provide more options of therapeutic interventions. The purpose of non-classical treatment strategies for AD is to decrease skin inflammation, re-direct the imbalanced immune polarization, and induce immune tolerance to allergens. Generally, the intervention for mouse model of AD can be classified into 1) monoclonal antibodies, 2) anti-oxidants, 3) allergen-specific immunotherapy, 4) herbal medicine, 5) treatment with materials extracted from food or micronutrients, 6) microbiota/probiotics, 7) bio-composites films, and 8) others. Since half of the patients with AD lack specific immunoglobulin E against allergens, the pathogenesis of different phenotypes still needs to be clarified. Through novel therapies such as cytokine-targeting therapy, miRNA or suppression of thymic stromal lymphopoietin, patients with AD could have better quality of life with less morbidity.

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“…JTE-052 inhibits JAK1, JAK2, JAK3 and Tyk2 enzymatic activity with 50% inhibitory concentrations of 2.8, 2.6, 13 and 58 nmol/L, respectively, and inhibits STAT phosphorylation. [14,15] For in-vitro studies, test compounds were dissolved in dimethyl sulfoxide (DMSO) and added at a final DMSO concentration of less than 0.1%. 8 For in-vivo studies, JTE-052 was suspended in 0.5% methylcellulose (Wako, Japan) and was orally administered to mice once a day.…”

Section: Drugs and Reagentsmentioning

confidence: 99%