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D.-Q. Li, X. Zheng, L. Zhang, P. Ma, N. Zhou, M. A. Cunningham, C. S. De Paiva, S. C. Pflugfelder; Thymic Stromal Lymphopoietin Serves as a Potential Biomarker for Allergic Inflammation in the Ocular Surface. Invest. Ophthalmol. Vis. Sci. 2010;51(13):4827.
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Thymic stromal lymphopoietin (TSLP) is a recently identified epithelium-derived pro-allergic cytokine. This study was to explore a potential role of TSLP serving as a biomarker for ocular allergic inflammation.
TSLP and its downstream molecules were evaluated in ocular surface of human patients with atopic conjunctivitis and in experimental allergic conjunctivitis (EAC) mice induced by short ragweed (SRW). Dendritic cells (DCs) were induced from mouse bone marrow. Primary human corneal epithelial cells were cultured for investigating the TSLP regulation and pathways. The mRNA expression was determined by reverse transcription and real time PCR. The protein production was measured by ELISA, immunohistochemical staining and Western blot analysis.
TSLP and OX40L were highly detected in conjunctival impression cytology samples from atopic conjunctivitis patients. In the SRW-induced EAC mice, TSLP transcripts and immunoreactivity significantly increased in the corneal and conjunctival epithelia; and the CD11c+ and OX40L+ immunoreactive DCs largely infiltrated the conjunctiva with increased mRNA levels of CD11c, TSLPR and OX40L detected in the corneal epithelia, conjunctiva and cervical lymph nodes. Th2 cell infiltration was evidenced by increased transcripts and immunoreactivity of CD4, IL-4, IL-5 and IL-13 in the conjunctiva, accompanied by increased expression of OX40, STAT6 and GATA3 in EAC mice. In an in vitro culture model, exogenous TSLP directly induced OX40L expression by murine bone marrow-derived DCs. Interestingly, TSLP was dramatically stimulated in human corneal epithelial cells exposed to microbial ligands (dsRNA, flagellin, FSL, etc), and proinflammatory cytokines (IL-1β and TNF-α) through toll-like receptor (TLR) and NFkB pathways. Their stimulation was significantly synergized by Th2 cytokines (IL-13 and IL-4) and SRW, but suppressed by Th1 cytokine IFNγ. Furthermore, TSLP was found to stimulate IL-33, a ligand of ST2, in corneal epithelial cells; and the expression of IL-33 and its receptor ST2 was upregulated in the conjunctiva and cervical lymph nodes of the EAC mice.
This study provides new findings regarding the role of local mucosal epithelial cells in initiation of ocular allergic inflammation by producing a novel pro-allergic cytokine TSLP, which activates DCs to prime Th2 differentiation through TSLP-OX40L and IL-33-ST2 signaling pathways.
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