Glucocorticoids inhibit double-stranded RNA-induced thymic stromal lymphopoietin release from keratinocytes in an atopic cytokine milieu more effectively than tacrolimus.
BACKGROUND
Thymic stromal lymphopoietin (TSLP), highly expressed by keratinocytes in skin lesions in atopic dermatitis and bronchial epithelial cells in asthma, plays a key role in allergic diseases. Double-stranded RNA (dsRNA) stimulates keratinocytes to release TSLP in vitro.


OBJECTIVE
To examine the potential of glucocorticoids and calcineurin inhibitors to suppress dsRNA-induced release of TSLP from keratinocytes.


METHODS
Primary human kerarinocytes were stimulated with dsRNA in the presence of IL-4, IL-13 and TNF-alpha. TSLP release was measured by ELISA. The effects of glucocorticoids and 2 calcineurin inhibitors, cyclosporin A and FK506/tacrolimus, were analyzed.


RESULTS
The glucocorticoids inhibited dsRNA-induced release of TSLP. The inhibitory effect became saturated (50-70% reduction) at concentrations higher than 10(-10)M. Cyclosporin A inhibited the release of TSLP by 50-60% at 10(-5) and 10(-4)M. FK506 had no effect at 10(-5)M or less, but almost completely inhibited the release of TSLP at 10(-4)M. No synergistic effect was obtained with a glucocorticoid plus either of the calcineurin inhibitors. An additive inhibitory effect was obtained with a glucocorticoid plus 10(-5)M cyclosporin A. Glucocorticoid inhibited dsRNA-induced TSLP transcription in the absence of Th2/TNF cytokines.


CONCLUSIONS
Glucocorticoids inhibited the dsRNA-induced release of TSLP in the atopic cytokine milieu at much lower concentrations than calcineurin inhibitors, suggesting that they could be effective in the treatment of atopic dermatitis when exogenous or endogenous dsRNA is involved in the pathogenesis. In addition, the in vitro system established in this study would be useful for screening of therapeutic reagents which target TSLP expression.
Le
Tuan Anh
TA
Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Tokyo, Japan.
Takai
Toshiro
T
Vu
Anh Tuan
AT
Kinoshita
Hirokazu
H
Ikeda
Shigaku
S
Ogawa
Hideoki
H
Okumura
Ko
K
D065095:Calcineurin Inhibitors; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D003876:Dermatitis, Atopic / Q000276:immunology; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D012330:RNA, Double-Stranded / Q000378:metabolism / Q000494:pharmacology*; D016559:Tacrolimus / Q000494:pharmacology*; D000094632:Thymic Stromal Lymphopoietin
D065095:Calcineurin Inhibitors; D016207:Cytokines; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D012330:RNA, Double-Stranded; D016559:Tacrolimus; D000094632:Thymic Stromal Lymphopoietin