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Nobuyuki Ebihara, Akira Matsuda, Shinji Nakamura, Hironori Matsuda, Akira Murakami; Role of the IL-6 Classic- and Trans-Signaling Pathways in Corneal Sterile Inflammation and Wound Healing. Invest. Ophthalmol. Vis. Sci. 2011;52(12):8549-8557. doi: https://doi.org/10.1167/iovs.11-7956.
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To investigate the role of the IL-6 classic- and trans-signaling pathways in corneal sterile inflammation and wound healing.
To assess the production of inflammatory molecules by corneal fibroblasts treated with supernatant derived from necrotic corneal epithelial cells, the authors used an antibody array. Expressions of membrane IL-6 receptor (mIL-6R) and soluble IL-6R (SIL-6R) by fibroblasts and epithelial cells were detected with flow cytometry and RT-PCR. Expressions of signal transducer and activator of transcription 3 (STAT3), vascular endothelial growth factor (VEGF), and monocyte chemotactic protein-1 (MCP-1) by fibroblasts stimulated with IL-6 alone or IL-6/SIL-6R were determined by ELISA. The effect of IL-6 or IL-6/SIL-6R on epithelial cell migration was investigated in vitro by the scratch assay, whereas expressions of IL-6R and S100 A4 in the corneas of mice were detected by immunohistochemistry after incision of the corneal stroma.
IL-1 derived from necrotic corneal epithelial cells induced the production of IL-6 by corneal fibroblasts. mIL-6R and SIL-6R mRNAs were expressed by both types of cells, although IL-6R protein at the cell surface was expressed only by epithelial cells. Expression of gp130 was detected in both types of cells. Activation of the IL-6 trans-signaling pathway induced the phosphorylation of STAT3, resulting in an increase of VEGF and MCP-1 production by corneal fibroblasts. Activation of the IL-6 classic-signaling pathway promoted the migration of corneal epithelial cells. IL-6R expression was also detected in activated fibroblasts and basal cells of the epithelium during the processes of wound healing in vivo.
The IL-6 classic- and trans-signaling pathways have an important role in corneal sterile inflammation and wound healing.
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