TLR-mediated induction of pro-allergic cytokine IL-33 in ocular mucosal epithelium

Lili Zhang, Rong Lu, Guiqiu Zhao, Stephen C Pflugfelder, De-Quan Li

Research output: Contribution to journalArticlepeer-review

70 Scopus citations


Interleukin (IL) 33 has been recently identified as a ligand to the ST2 receptor that mediates Th2-dominant allergic inflammation. The purpose of this study was to explore the role of toll-like receptor (TLR)-mediated innate immunity in IL-33 induction by mucosal epithelium. Human corneal tissues and cultured primary human corneal epithelial cells (HCECs) were treated with a variety of viral or bacterial components without or with different inhibitors to evaluate the IL-33 regulation and signaling pathways. The level of mRNA expression was determined by reverse transcription and real time PCR, and protein was measured by ELISA, immunostaining and Western blotting. IL-33 mRNA and protein were largely induced by various microbial components, mainly by polyI:C and flagellin, the ligands to TLR3 and TLR5, respectively in human corneal epithelium ex vivo and in vitro cultures. Pro-IL-33 protein was normally restricted inside cells, and could be secreted outside when activated by ATP. The PolyI:C induced IL-33 production was blocked by TLR3 antibody or TRIF Inhibitory peptide, while flagellin stimulated IL-33 was blocked by TLR5 antibody or MyD88 Inhibitory peptide. Interestingly, IκB-α inhibitor (BAY11-7082) or NF-κB inhibitor (quinazoline) blocked NF-κB p65 protein nuclear translocation, and suppressed IL-33 production induced by PolyI:C and flagellin. These findings demonstrate that IL-33, an epithelium-derived pro-allergic cytokine, is induced by microbial ligands through TLR-mediated innate signaling pathways, suggesting a possible role of mucosal epithelium in Th2-dominant allergic inflammation.

Original languageEnglish (US)
Pages (from-to)1383-91
Number of pages9
JournalInternational Journal of Biochemistry and Cell Biology
Issue number9
StatePublished - Sep 2011
Externally publishedYes


  • Cells, Cultured
  • Cornea/cytology
  • Diglycerides/immunology
  • Epithelium, Corneal/immunology
  • Flagellin/immunology
  • Gene Expression/drug effects
  • Gene Expression Profiling
  • Humans
  • I-kappa B Kinase/genetics
  • Immunity, Innate
  • Interleukin-33
  • Interleukins/genetics
  • Lipopolysaccharides/immunology
  • NF-kappa B/metabolism
  • Oligopeptides/immunology
  • Poly I-C/immunology
  • Primary Cell Culture
  • Quinolines/pharmacology
  • Signal Transduction
  • Toll-Like Receptors/agonists


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