Cytokine milieu modulates release of thymic stromal lymphopoietin from human keratinocytes stimulated with double-stranded RNA.
BACKGROUND
Thymic stromal lymphopoietin (TSLP) plays a key role in allergic diseases, such as atopic dermatitis (AD) and asthma. TSLP is highly expressed by keratinocytes in skin lesions of patients with AD, but environmental triggers for its release from keratinocytes with endogenous factors are not well understood. Patients with AD, in whom allergic sensitization is already established, are susceptible to viral dissemination.


OBJECTIVE
We investigated TSLP's release from primary human keratinocytes stimulated with a Toll-like receptor (TLR) 3 ligand, polyinosinic-polycytidylic acid, which mimics viral double-stranded RNA (dsRNA), and its modulation by cytokines.


METHODS
Primary human keratinocytes were stimulated with TLR ligands, cytokines, or both. TSLP released into culture supernatants was measured by means of ELISA.


RESULTS
Stimulation of keratinocytes with dsRNA induced release of TSLP and upregulated gene expression of TSLP and other cytokines and chemokines. The release of TSLP was enhanced by the addition of IL-4, IL-13, and/or TNF-alpha. With or without the T(H)2/TNF cytokines, the dsRNA-induced release of TSLP was upregulated by IFN-alpha and IFN-beta and suppressed by IFN-gamma, TGF-beta, or IL-17.


CONCLUSIONS
The effect of the TLR3 ligand on keratinocytes suggests contribution of viral dsRNA to skin inflammations under the influence of a cytokine milieu. The results imply that viral dsRNA and a T(H)2 cytokine milieu might promote T(H)2-type inflammation through an induction of TSLP expression, suggesting that a vicious cycle exists between AD with T(H)2-type inflammation and viral infections and a possible blockade of this cycle by other cytokine milieus provided by cells, such as T(H)1, regulatory T, and T(H)17 cells.
Kinoshita
Hirokazu
H
Atopy (Allergy) Research Center, Juntendo University School of Medicine, Tokyo, Japan.
Takai
Toshiro
T
Le
Tuan Anh
TA
Kamijo
Seiji
S
Wang
Xiao Ling
XL
Ushio
Hiroko
H
Hara
Mutsuko
M
Kawasaki
Junko
J
Vu
Anh Tuan
AT
Ogawa
Takasuke
T
Gunawan
Hendra
H
Ikeda
Shigaku
S
Okumura
Ko
K
Ogawa
Hideoki
H
D001249:Asthma / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D003876:Dermatitis, Atopic / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007369:Interferon Inducers / Q000276:immunology / Q000494:pharmacology*; D008024:Ligands; D011070:Poly I-C / Q000276:immunology* / Q000494:pharmacology; D012330:RNA, Double-Stranded / Q000276:immunology / Q000494:pharmacology*; D051196:Toll-Like Receptor 3 / Q000819:agonists / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology; D000094632:Thymic Stromal Lymphopoietin
D016207:Cytokines; D007369:Interferon Inducers; D008024:Ligands; D012330:RNA, Double-Stranded; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D011070:Poly I-C; D000094632:Thymic Stromal Lymphopoietin