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Jing Lin, Guiqiu Zhao, Lili Zhang; Role of ST2 Signaling in IL-33 Induced Inflammation in Human Corneal Epithelium. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5996.
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Interleukin (IL) 33, a member of IL-1 cytokine family, is well known to promote Th2 type immune responses by signaling through its receptor ST2. However, it is not clear whether ST2 is expressed by mucosal epithelium, and how it responds to IL-33 to induce inflammatory mediator. This study was to explore the expression and functional role of ST2 signaling in IL-33 stimulated production of proinflammatory cytokines by human corneal epithelium.
Human corneal tissues and cultured primary human corneal epithelial cells (HCECs) were treated with IL-33 in different concentrations without or with different inhibitors to evaluate the expression, location and signaling pathways of ST2 in regulating production of inflammatory cytokines and chemokine. The mRNA expression was determined by reverse transcription and real time PCR, and protein production was measured by ELISA, immunohistochemical and immunofluorescent staining.
In ex vivo donor corneal epithelium, ST2 protein was detected to be located in superficial layers, and its immunoreactivity was enhanced by multiple layers of corneal epithelium exposed to IL-33. Primary HCECs also expressed ST2 at both mRNA and protein levels, which were stimulated in a dose-dependent manner when the cells exposed to IL-33. IL-33 significantly stimulated production of inflammatory cytokines (TNF-α, IL-1β and IL-6) and chemokine IL-8 by HCECs at both mRNA and protein levels. The stimulated production of these inflammatory mediators by IL-33 was blocked by ST2 antibody or soluble ST2 protein. Interestingly, IκB-α inhibitor BAY11-7082 or NF-κB activation inhibitor quinazoline blocked the nuclear translocation of NF-κB p65 protein, and further suppressed the production of these inflammatory cytokines and chemokine induced by IL-33.
These findings demonstrate for the first time that ST2 is present in human corneal epithelial cells, and ST2 signaling plays an important role in regulating IL-33 induced inflammatory responses, suggesting that IL-33 and ST2 could become novel molecular targets for the intervention of inflammatory diseases in ocular surface.
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