Research
Differential effects of cytokines and corticosteroids on Toll-like receptor 2 expression and activity in human airway epithelia
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* Corresponding author: Paul B McCray paul-mccray@uiowa.edu
1 Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA USA
2 Department of Opthalmology, Carver College of Medicine, University of Iowa, Iowa City, IA USA
3 Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA USA
4 Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, IA USA
5 College of Engineering, University of Iowa, Iowa City, IA USA
Respiratory Research 2009, 10:96 doi:10.1186/1465-9921-10-96
Published: 16 October 2009Abstract
Background
The recognition of microbial molecular patterns via Toll-like receptors (TLRs) is critical for mucosal defenses.
Methods
Using well-differentiated primary cultures of human airway epithelia, we investigated the effects of exposure of the cells to cytokines (TNF-α and IFN-γ) and dexamethasone (dex) on responsiveness to the TLR2/TLR1 ligand Pam3CSK4. Production of IL-8, CCL20, and airway surface liquid antimicrobial activity were used as endpoints.
Results
Microarray expression profiling in human airway epithelia revealed that first response cytokines markedly induced TLR2 expression. Real-time PCR confirmed that cytokines (TNF-α and IFN-γ), dexamethasone (dex), or cytokines + dex increased TLR2 mRNA abundance. A synergistic increase was seen with cytokines + dex. To assess TLR2 function, epithelia pre-treated with cytokines ± dex were exposed to the TLR2/TLR1 ligand Pam3CSK4 for 24 hours. While cells pre-treated with cytokines alone exhibited significantly enhanced IL-8 and CCL20 secretion following Pam3CSK4, mean IL-8 and CCL20 release decreased in Pam3CSK4 stimulated cells following cytokines + dex pre-treatment. This marked increase in inflammatory gene expression seen after treatment with cytokines followed by the TLR2 ligand did not correlate well with NF-κB, Stat1, or p38 MAP kinase pathway activation. Cytokines also enhanced TLR2 agonist-induced beta-defensin 2 mRNA expression and increased the antimicrobial activity of airway surface liquid. Dex blocked these effects.
Conclusion
While dex treatment enhanced TLR2 expression, co-administration of dex with cytokines inhibited airway epithelial cell responsiveness to TLR2/TLR1 ligand over cytokines alone. Enhanced functional TLR2 expression following exposure to TNF-α and IFN-γ may serve as a dynamic means to amplify epithelial innate immune responses during infectious or inflammatory pulmonary diseases.