Role of the IL-6 classic- and trans-signaling pathways in corneal sterile inflammation and wound healing
Abstract
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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IL6 contributes to wound healing both via proinflammatory actions and by promoting cell migration.
“IL6 is important in wound healing, not only through proinflammatory effects but also by promoting cell migration (Ebihara, et al., 2011,Nasole, et al., 2014).”
From A potential endophenotype for Alzheimer's disease: cerebrospinal fluid clusterin (2016) · cites this paper as Ebihara, et al., 2011
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Self-citation
- Authors
- Ebihara, N., Matsuda, A., Nakamura, S., Matsuda, H., & Murakami, A.
- Affiliations
- Juntendo University (JP)
- From the Departments of Ophthalmology and
- Immunology, and
- Venue
- Investigative Opthalmology & Visual Science
- Published
- 2011-11-01
- Volume
- 52
- Issue
- 12
- Pages
- 8549
- ISSN
- 0146-0404 (ISSN-L)
- 1552-5783
- OpenAlex
- W2079195366
- Cited by
- 147
- References
- 42
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 13 · 2023: 12 · 2022: 10 · 2021: 13 · 2020: 9 · 2019: 10 · 2018: 7 · 2017: 15 · 2016: 7 · 2015: 12 · 2014: 7 · 2013: 15 · 2012: 1
- FWCI
- 3.62
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Investigative Ophthalmology & Visual Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (21592239, 22659313)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Corneal Surgery and Treatments
- Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
- Keywords
- interleukin-6, IL-6 trans-signaling, corneal wound healing, corneal fibroblasts, corneal epithelial cells, soluble IL-6 receptor, STAT3 phosphorylation, vascular endothelial growth factor, MCP-1, gp130, epithelial cell migration, interleukin-1, S100A4
- MeSH terms
- Cell Movement, Epithelial Cells, Humans, Keratitis, Necrosis, Phosphorylation, Wound Healing, Signal Transduction, Interleukin-6, Chemokine CCL2, Epithelium, Corneal, Receptors, Interleukin-6, Vascular Endothelial Growth Factor A, STAT3 Transcription Factor, Cytokine Receptor gp130, Corneal Keratocytes, Primary Cell Culture
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