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Allergy-Immunology Division, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
Thymic stromal lymphopoietin (TSLP) is elevated in asthma and triggers dendritic cell-mediated activation of Th2 inflammatory responses. Although TSLP has been shown to be produced mainly by airway epithelial cells, the regulation of epithelial TSLP expression has not been extensively studied. We investigated the expression of TSLP in cytokine- or TLR ligand-treated normal human bronchial epithelial cells (NHBE). The mRNA for TSLP was significantly up-regulated by stimulation with IL-4 (5.5-fold) and IL-13 (5.3-fold), weakly up-regulated by TNF-
, TGF-
, and IFN-, and not affected by IFN-
in NHBE. TSLP mRNA was only significantly up-regulated by the TLR3 ligand (dsRNA) among the TLR ligands tested (66.8-fold). TSLP was also induced by in vitro infection with rhinovirus. TSLP protein was detected after stimulation with dsRNA (120 ± 23 pg/ml). The combination of TNF- and IL-4 produced detectable levels of TSLP protein (40 ± 13 pg/ml). In addition, TSLP was synergistically enhanced by a combination of IL-4 and dsRNA (mRNA; 207-fold, protein; 325 ± 75 pg/ml). The induction of TSLP by dsRNA was dependent upon NF-
B and IFN regulatory factor 3 (IRF-3) signaling via TLR3 as indicated by a study with small interfering RNA. The potent topical glucocorticoid fluticasone propionate significantly suppressed dsRNA-dependent TSLP production in NHBE. These results suggest that the expression of TSLP is induced in airway epithelial cells by stimulation with the TLR3 ligand and Th2 cytokines and that this response is suppressed by glucocorticoid treatment. This implies that respiratory viral infection and the recruitment of Th2 cytokine producing cells may amplify Th2 inflammation via the induction of TSLP in the asthmatic airway.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by National Institutes of Health Grants R01 HL068546 and R01 HL078860 and by a grant from the Ernest S. Bazley Trust. A.K. is the recipient of a 2007 Strategic Training in Allergy Research (ST*AR) Program Award from the American Academy of Allergy, Asthma, and Immunology.
2 Address correspondence and reprint requests to Dr. Robert P. Schleimer, Allergy-Immunology Division, Northwestern University Feinberg School of Medicine, 240 East Huron, Chicago, IL 60611. E-mail address: rpschleimer{at}northwestern.edu
3 Abbreviations used in this paper: TSLP, thymic stromal lymphopoietin; DC, dendritic cells; FP, fluticasone propionate; FSL-1, Cys-Gly-Asp-Pro-Lys-His-Pro-Lys-Ser-Phe; IFNAR, IFN or receptor; IRF-3, IFN regulatory factor 3; LTA, lipoteichoic acid; MDA5, melanoma differentiation-associated gene 5; mDC, myeloid DC; MOI, multiplicity of infection; NFKB1, NF-B p50; NHBE, normal human bronchial epithelial cell; Pam3CSK4, N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2-RS)-propyl]-[R]-Cys-[S]-Ser-[S]-Lys4 trihydrochloride; PGN, peptidoglycan; PKR, dsRNA-dependent protein kinase; RELA, NF-B p65; RIG-I, retinoic acid-inducible gene I; RV16, rhinovirus serotype 16; RXRA, retinoid X receptor A; siRNA, small interfering RNA; TSLPR, TSLP receptor.
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