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Respir Res. 2009 Oct 16;10:96. doi: 10.1186/1465-9921-10-96.

Differential effects of cytokines and corticosteroids on toll-like receptor 2 expression and activity in human airway epithelia.

Author information

  • 1Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA, USA. audra.winder@marshfieldclinic.org

Abstract

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-alpha and IFN-gamma) 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-alpha and IFN-gamma), 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-kappaB, 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-alpha and IFN-gamma may serve as a dynamic means to amplify epithelial innate immune responses during infectious or inflammatory pulmonary diseases.

PMID:
19835594
[PubMed - indexed for MEDLINE]
PMCID:
PMC2772856
Free PMC Article

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