Abstract
Purpose: :
Interleukin (IL) 33, a new IL-1 family cytokine, has been recently identified as a ligand to ST2 receptor for Th2 response, and known to mediate allergic inflammatory diseases. This study was to explore the toll-like receptor (TLR)-mediated induction of IL-33 by human corneal epithelial cells and its potential role in ocular allergic inflammation.
Methods: :
IL-33 and its receptor ST2 were determined in ocular surface from human patients with atopic conjunctivitis and in experimental allergic conjunctivitis (EAC) mice induced by short ragweed (SRW) with topical challenges. Primary human corneal epithelial cells were cultured to evaluate the regulation of IL-33 and its pathways. The mRNA expression was determined by reverse transcription and real time PCR with TaqMan primers and probes. The protein production was measured by ELISA, Luminex immunobead assays and immunohistochemical staining.
Results: :
IL-33 and its receptor ST2 were highly detected in conjunctival impression cytology specimen from atopic conjunctivitis patients. In the SRW-induced EAC mice, IL-33 and ST2 transcripts significantly increased in the corneal/conjunctival epithelia and/or cervical lymph nodes; and the CD11c+ dendritic cells (DCs) and CD4+ Th2 cells largely infiltrated the conjunctiva with increased transcripts and immunoreactivity of CD11c, CD4, IL-4, IL-5 and IL-13 detected in the conjunctiva and cervical lymph nodes. In an in vitro culture model, IL-33 was induced in human corneal epithelial cells exposed to various microbial components (dsRNA, flagellin and FSL-1, the ligands to TLR-3, -5 and -2/6, respectively) and proinflammatory cytokines (IL-1β and TNF-α) through TLR and NFkB pathways. Furthermore, IL-33 stimulated expression of inflammatory mediators (TNF-α, IL-6, RANTS, MMP-1, MMP-3 and MMP-9) by human corneal epithelial cells. Experiments are going on to investigate the direct effects of IL-33 on DCs and CD4+ T cells from normal and EAC mice.
Conclusions: :
These findings demonstrated that IL-33, an inflammatory cytokine, is induced by human corneal epithelial cells through TLR-mediated innate response, and it promotes production of inflammatory mediators. Interestingly, IL-33 plays an important role in ocular allergic inflammation through activating ST2 signaling for Th2 cytokine response.
Keywords: immunomodulation/immunoregulation • inflammation • cornea: epithelium