Viral stimuli trigger exaggerated thymic stromal lymphopoietin expression by chronic obstructive pulmonary pisease epithelium: role of endosomal TLR3 and cytosolic RIG-I-Like helicases

Calvén, Jenny, Yudina, Yulyana, Hallgren, Oskar, Westergren-Thorsson, Gunilla, Davies, Donna E., Brandelius, Angelica and Uller, Lena (2011) Viral stimuli trigger exaggerated thymic stromal lymphopoietin expression by chronic obstructive pulmonary pisease epithelium: role of endosomal TLR3 and cytosolic RIG-I-Like helicases. Journal of Innate Immunity. (doi:10.1159/000329131). (PMID:21691053) (In Press)

Abstract

Background: Rhinovirus (RV)-induced chronic obstructive pulmonary disease (COPD) exacerbations exhibit TH(2)-like inflammation. We hypothesized that RV-infected bronchial epithelial cells (BEC) overproduce TH(2)-switching hub cytokine, thymic stromal lymphopoietin (TSLP) in COPD. Methods: Primary BEC from healthy (HBEC) and from COPD donors (COPD-BEC) were grown in 12-well plates, infected with RV16 (0.5-5 MOI) or stimulated with agonists for either toll-like receptor (TLR) 3 (dsRNA, 0.1-10 ?g/ml) or RIG-I-like helicases (dsRNA-LyoVec, 0.1-10 ?g/ml). Cytokine mRNA and protein were determined (RTqPCR; ELISA). Results: dsRNA dose-dependently evoked cytokine gene overproduction of TSLP, CXCL8 and TNF-? in COPD-BEC compared to HBEC. This was confirmed using RV16 infection. IFN-? induction did not differ between COPD-BEC and HBEC. Endosomal TLR3 inhibition by chloroquine dose-dependently inhibited dsRNA-induced TSLP generation and reduced generation of CXCL8, TNF-?, and IFN-?. Stimulation of cytosolic viral sensors (RIG-I-like helicases) with dsRNA-LyoVec increased production of CXCL8, TNF-?, and IFN-?, but not TSLP. Conclusions: Endosomal TLR3-stimulation, by dsRNA or RV16, induces overproduction of TSLP in COPD-BEC. dsRNA- and RV-induced overproduction of TNF-? and CXCL8 involves endosomal TLR3 and cytosolic RIG-I-like helicases and so does the generation of IFN-? in COPD-BEC. RV16 and dsRNA-induced epithelial TSLP may contribute to pathogenic effects at exacerbations and development of COPD.

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Contributors

Author: Donna E. Davies

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