Involvement of macrophage chemotactic protein-1 and interleukin-1beta during inflammatory but not basic fibroblast growth factor-dependent neovascularization in the mouse cornea.
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-1beta, on macrophage recruitment and neovascularization. Both MCP-1, IL-1beta 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-1beta was located in corneal epithelial cells and infiltrating inflammatory cells. In addition, double staining of corneas with antibodies specific for monocytes/macrophages and IL-1beta revealed that IL-1beta was found in infiltrating monocytes/macrophages at Day 2 after cauterization. Both IL-1beta 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-1beta 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-1beta 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-1beta leading to inflammatory neovascularization. In addition, the IL-1beta and MCP-1 released from the corneal epithelial cells may directly induce corneal neovascularization.
Yoshida
Shigeo
S
Department of Ophthalmology, Kyushu University Graduate School of Medicine, Fukuoka, Japan.
Yoshida
Ayako
A
Matsui
Hironori
H
Takada
Yu-Ichiro
Y
Ishibashi
Tatsuro
T
D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D054407:Chemokine CCL4; D003315:Cornea / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004357:Drug Synergism; D019573:Epithelium, Corneal / Q000378:metabolism / Q000473:pathology; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000502:physiology*; D017403:In Situ Hybridization; D007375:Interleukin-1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D019402:Macrophage Inflammatory Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D019138:Antibodies, Blocking; D054407:Chemokine CCL4; D007375:Interleukin-1; D019402:Macrophage Inflammatory Proteins; D012333:RNA, Messenger; D016222:Fibroblast Growth Factor 2