Involvement of Macrophage Chemotactic Protein-1 and Interleukin-1β During Inflammatory but Not Basic Fibroblast Growth Factor–Dependent Neovascularization in the Mouse Cornea

Abstract

SUMMARY:Corneal neovascularization develops in several pathologic conditions, but its underlying mechanisms remain elusive. We used a mouse inflammatory corneal model (corneas cauterized with silver nitrate) and assessed the role of monocyte/macrophage-attracting factors, macrophage chemotactic protein-1 (MCP-1), and a proinflammatory cytokine, IL-1␤, on macrophage recruitment and neovascularization. Both MCP-1, IL-1␤ protein, and mRNA levels increased markedly 12 hours after the chemical cauterization. In situ hybridization showed that MCP-1 was located in corneal epithelial cells, and IL-1␤ was located in corneal epithelial cells and infiltrating inflammatory cells. In addition, double staining of corneas with antibodies specific for monocytes/macrophages and IL-1␤ revealed that IL-1␤ was found in infiltrating monocytes/macrophages at Day 2 after cauterization. Both IL-1␤ and MCP-1 induced neovascularization in a rat cornea model, and the cauterization-induced corneal neovascularization was partially inhibited by subconjunctival injection of anti-IL-1␤ or anti-MCP-1. Coadministration of two antibodies inhibited corneal neovascularization slightly more than that by the administration of each. In contrast, administration of the anti-MCP-1 or anti-IL-1␤ showed minimal inhibition of basic fibroblast growth factor-driven corneal neovascularization by mouse cornea assay. Cauterized corneas treated with anti-MCP-1 antibody had significantly fewer monocytes/macrophages than control. These results indicate the existence of distinct monocyte/macrophage-involved angiogenic pathways in mouse cornea, in which MCP-1 released from corneal epithelial cells attracts monocytes/macrophages into the cornea, where they release IL-1␤ leading to inflammatory neovascularization. In addition, the IL-1␤ and MCP-1 released from the corneal epithelial cells may directly induce corneal neovascularization. (Lab Invest 2003, 83:927-938).

Induction of IL-8, MCP-1, and bFGF by TNF-α in retinal glial cells: implications for retinal neovascularization during post-ischemic inflammation

“…The primers were, for IL-8: The PCR conditions were 10 min at 94C, followed by 35 cycles at 72C for 20 s, 94C for 30 s, and 60C for 30 s, with a final extension step at 72C for 5 min. The resulting PCR fragments were confirmed by direct dideoxynucleotide chain termination [18,21].…”

Potential Inhibitory Effect of LASSBio-596, a New Thalidomide Hybrid, on Inflammatory Corneal Angiogenesis in Rabbits

“…The main stimuli for neovascularization are inflammation, hypoxia and limbic stem cell destruction [9]. There is exacerbation of the angiogenic process in various other diseases, namely diabetic retinopathy, macular degeneration and solid tumors [4,5,6,7,8,9]. For the treatment of these diseases, several drugs with antiangiogenic properties were identified, and their mechanisms of action were studied.…”

“…Corneal neovascularization from the limbic vascular plexus is a common feature of several diseases of the cornea, either of infectious, traumatic, degenerative or inflammatory origin [6,7,8]. The main stimuli for neovascularization are inflammation, hypoxia and limbic stem cell destruction [9].…”

FGF-2 Induced by Interleukin-1β through the Action of Phosphatidylinositol 3-Kinase Mediates Endothelial Mesenchymal Transformation in Corneal Endothelial Cells

“…IL-1␤ also has a crucial role in the regulation of inflammation and wound healing on the ocular surface (13)(14)(15)(16)(17)(18). Numerous studies report that both IL-1␣ and IL-1␤ orchestrate the inflammatory process by inducing the production and release of secondary cytokines; IL-1␤ stimulates the expression of a variety of genes necessary for the wound repair processes (19 -22).…”