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Infiltration of COX-2–expressing macrophages is a prerequisite for IL-1β–induced neovascularization and tumor growth
Shintaro Nakao, … , Michihiko Kuwano, Mayumi Ono
Shintaro Nakao, … , Michihiko Kuwano, Mayumi Ono
Published November 1, 2005
Citation Information: J Clin Invest. 2005;115(11):2979-2991. https://doi.org/10.1172/JCI23298.
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Research Article Angiogenesis Article has an altmetric score of 3

Infiltration of COX-2–expressing macrophages is a prerequisite for IL-1β–induced neovascularization and tumor growth

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Abstract

Inflammatory angiogenesis is a critical process in tumor progression and other diseases. The inflammatory cytokine IL-1β promotes angiogenesis, tumor growth, and metastasis, but its mechanisms remain unclear. We examined the association between IL-1β–induced angiogenesis and cell inflammation. IL-1β induced neovascularization in the mouse cornea at rates comparable to those of VEGF. Neutrophil infiltration occurred on day 2. Macrophage infiltration occurred on days 4 and 6. The anti–Gr-1 Ab-induced depletion of infiltrating neutrophils did not affect IL-1β– or VEGF-induced angiogenesis. The former was reduced in monocyte chemoattractant protein-1–deficient (MCP-1–/–) mice compared with wild-type mice. After day 4, clodronate liposomes, which kill macrophages, reduced IL-1β–induced angiogenesis and partially inhibited VEGF-induced angiogenesis. Infiltrating macrophages near the IL-1β–induced neovasculature were COX-2 positive. Lewis lung carcinoma cells expressing IL-1β (LLC/IL-1β) developed neovasculature with macrophage infiltration and enhanced tumor growth in wild-type but not MCP-1–/– mice. A COX-2 inhibitor reduced tumor growth, angiogenesis, and macrophage infiltration in LLC/IL-1β. Thus, macrophage involvement might be a prerequisite for IL-1β–induced neovascularization and tumor progression.

Authors

Shintaro Nakao, Takashi Kuwano, Chikako Tsutsumi-Miyahara, Shu-ichi Ueda, Yusuke N. Kimura, Shinjiro Hamano, Koh-hei Sonoda, Yasuo Saijo, Toshihiro Nukiwa, Robert M. Strieter, Tatsuro Ishibashi, Michihiko Kuwano, Mayumi Ono

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Figure 2

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The role of neutrophils in IL-1β– or VEGF-induced angiogenesis. (A) BALB...
The role of neutrophils in IL-1β– or VEGF-induced angiogenesis. (A) BALB/c mice received 200 μg neutralizing anti–Gr-1 mAb i.p. on days –1, 1, 3, and 5. Hydron pellets containing IL-1β (30 ng) or VEGF (200 ng) were implanted into the corneas on day 0. Corneal vessels in the region of the pellet implants were photographed at the indicated time points. (B) Anti–Gr-1 mAb did not suppress IL-1β– or VEGF-induced corneal neovascularization. Corneal neovascularization 6 days after treatment with anti–Gr-1 mAb (black bars) or control IgG (white bars) was quantified by area, in mm2. The bars show means ± SD of independent experiments (n = 3 or 4). (C) Corneas implanted with IL-1β stained by H&E at the indicated time points. Anti–Gr-1 mAb did not affect IL-1β–induced corneal edema on day 2. (D) FACS analysis of infiltrating cells after IL-1β implantation (n = 5) and treatment with anti–Gr-1 mAb or control IgG at the indicated times. The cells were stained with PE-CD11b mAb or FITC–Gr-1. The percentages of CD11b+Gr-1+ cells in IL-1β–implanted corneas of anti–Gr-1 mAb-treated mice were 0.25% ± 0.22% (day 2), 0.11% ± 0.1% (day 4), and 0.28% ± 0.37% (day 6). (E) FACS analysis of infiltrating cells from 5 IL-1β–implanted corneas treated with anti–Gr-1 mAb or control IgG at the indicated times. Cells were stained with PE-CD11b mAb or FITC-F4/80. The percentages of CD11b+F4/80+ cells in IL-1β–implanted corneas of anti–Gr-1 mAb-treated mice were 1.71% ± 1.04% (day 2), 4.36% ± 1.20% (day 4), and 5.57% ± 1.34% (day 6).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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