title: Dexamethasone but not tacrolimus suppresses TNF-α-induced thymic stromal lymphopoietin expression in lesional keratinocytes of atopic dermatitis model.
abstract: BACKGROUND
  Thymic stromal lymphopoietin (TSLP) initiates the Th2-type allergic inflammation, and is thought to play an important role in the pathogenesis of atopic dermatitis (AD). TNF-α is a key cytokine which is involved in the pathophysiology of various inflammatory diseases, and the expression level is elevated in the sera and skin of patients with AD. In addition, TNF-α has been reported to induce TSLP expression in epidermal keratinocytes. Topical glucocorticoids and calcineurin inhibitors are safe and effective agents for AD, but the effects of these agents on TNF-α-induced TSLP expression are not fully understood.
  
  
  OBJECTIVE
  To investigate whether the glucocorticosteroid dexamethasone and the calcineurin inhibitor tacrolimus could affect TSLP expression induced by TNF-α in lesional keratinocytes of AD.
  
  
  METHODS
  The effects of topical dexamethasone and tacrolimus on TSLP expression were evaluated in an AD mouse model induced by repeated 2,4,6-trinitro-1-chlorobenzene application. Co-immunostaining for TSLP and TNF-α was performed using skin samples from AD patients and the mouse model. Normal human epidermal keratinocytes (NHEKs) were cultured with dexamethasone or tacrolimus in the presence of TNF-α to analyze TSLP expression.
  
  
  RESULTS
  Topical application of dexamethasone but not tacrolimus repressed TSLP expression in the mouse model. TSLP and TNF-α showed similar distribution pattern in epidermal keratinocytes of AD lesions and the mouse model. TSLP expression was induced by TNF-α via NF-κB in a dose-dependent and an autocrine and/or paracrine manner in NHEKs, which was significantly suppressed by dexamethasone but not by tacrolimus. Similarly to TSLP expression, IL-6, TNF-α, IL-8, and IL-36γ expression induced by TNF-α were significantly suppressed by dexamethasone but not by tacrolimus in NHEKs.
  
  
  CONCLUSIONS
  Dexamethasone but not tacrolimus suppresses the TSLP expression induced by TNF-α in lesional keratinocytes of AD model. Our observations uncover the unreported functional difference between topical glucocorticosteroids and calcineurin inhibitors in cutaneous inflammatory diseases.
authors.affiliation: Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Mizuno
authors.affiliation: Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan. Electronic address: zanemori@cc.okayama-u.ac.jp.
authors.forename: Shin
authors.initials: S
authors.lastname: Morizane
authors.affiliation: Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; Department of Plastic and Reconstructive Surgery, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Takiguchi
authors.affiliation: Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Iwatsuki
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D003876:Dermatitis, Atopic / Q000188:drug therapy*; D003907:Dexamethasone / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008807:Mice, Inbred BALB C; D016559:Tacrolimus / Q000494:pharmacology / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; D016559:Tacrolimus; D000094632:Thymic Stromal Lymphopoietin; C000721967:TSLP protein, mouse
keywords: Atopic dermatitis; Calcineurin inhibitor; Glucocorticosteroid; Psoriasis; Thymic stromal lymphopoietin; Tumor necrosis factor-α