Abstract
BackgroundBacterial and viral exacerbations play a crucial role in a variety of lung diseases including COPD or asthma. Since the lung epithelium is a major source of various inflammatory mediators that affect the immune response, we analyzed the inflammatory reaction of primary lung epithelial cells to different microbial molecules that are recognized by Toll-like receptors (TLR).MethodsThe effects of TLR ligands on primary small airway epithelial cells were analyzed in detail with respect to cytokine, chemokine and matrix metalloproteinase secretion. In addition, the regulation of the expression of TLRs and their adaptor proteins in small airway epithelial cells was investigated.ResultsOur data demonstrate that poly(I:C), a synthetic analog of viral dsRNA, mediated the strongest proinflammatory effects among the tested ligands, including an increased secretion of IL-6, IL-8, TNF-α, GM-CSF, GRO-α, TARC, MCP-1, MIP-3α, RANTES, IFN-β, IP-10 and ITAC as well as an increased release of MMP-1, MMP-8, MMP-9, MMP-10 and MMP-13. Furthermore, our data show that poly(I:C) as well as type-1 and type-2 cytokines have a pronounced effect on the expression of TLRs and molecules involved in TLR signaling in small airway epithelial cells. Poly(I:C) induced an elevated expression of TLR1, TLR2 and TLR3 and increased the gene expression of the general TLR adaptor MyD88 and IRAK-2. Simultaneously, poly(I:C) decreased the expression of TLR5, TLR6 and TOLLIP.ConclusionPoly(I:C), an analog of viral dsRNA and a TLR3 ligand, triggers a strong inflammatory response in small airway epithelial cells that is likely to contribute to viral exacerbations of pulmonary diseases like asthma or COPD. The pronounced effects of poly(I:C) on the expression of Toll-like receptors and molecules involved in TLR signaling is assumed to influence the immune response of the lung epithelium to viral and bacterial infections. Likewise, the regulation of TLR expression by type-1 and type-2 cytokines is important considering the impact of exogenous and endogenous TLR ligands on Th1 or Th2 driven pulmonary inflammations like COPD or asthma, respectively.
Highlights
Bacterial and viral exacerbations play a crucial role in a variety of lung diseases including COPD or asthma
Poly(I:C), an analog of viral dsRNA and a TLR3 ligand, triggers a strong inflammatory response in small airway epithelial cells that is likely to contribute to viral exacerbations of pulmonary diseases like asthma or COPD
The pronounced effects of poly(I:C) on the expression of Toll-like receptors and molecules involved in TLR signaling is assumed to influence the immune response of the lung epithelium to viral and bacterial infections
Summary
Bacterial and viral exacerbations play a crucial role in a variety of lung diseases including COPD or asthma. The lung epithelium is a major source of cytokine, chemokines and other inflammatory mediators that affect the adaptive and innate immune response and modulate inflammatory diseases like COPD or asthma [2]. Besides the induction of acute or chronic pulmonary inflammation, increased bacterial load and viral infections of the lung lead to severe exacerbations of diseases like COPD [3,4] or asthma [5] most probably due to a biased release of inflammatory mediators. TLR2 deficient mice have been shown to be highly susceptible to infection by Staphylococcus aureus, Borrelia burgdorferi and Streptococcus pneumonia [9,10] In addition to their prominent role in host response and innate immunity, TLRs play an important role for the adaptive immune system and the regulation of a Th1/Th2 balance [11]. In Th1 associated inflammatory disease like COPD, activation of TLRs either by exogenous or endogenous ligands is likely to result in disease exacerbations due to a biased proinflammatory response
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