Role of the IL-6 classic- and trans-signaling pathways in corneal sterile inflammation and wound healing

Nobuyuki Ebihara, Akira Matsuda, Shinji Nakamura, Hironori Matsuda, Akira Murakami
Investigative Ophthalmology & Visual Science 2011, 52 (12): 8549-57

PURPOSE: To investigate the role of the IL-6 classic- and trans-signaling pathways in corneal sterile inflammation and wound healing.

METHODS: 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.

RESULTS: 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.

CONCLUSIONS: The IL-6 classic- and trans-signaling pathways have an important role in corneal sterile inflammation and wound healing.

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