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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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Categories: Research Article Angiogenesis

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 7

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Enhancement of angiogenesis and macrophage infiltration by LLC/IL-1β was...
Enhancement of angiogenesis and macrophage infiltration by LLC/IL-1β was inhibited in MCP-1–/– mice (A) Representative photographs of CD31-stained sections from LLC tumors in wild-type or MCP-1–/– mice. Magnification, ×400. (B) CD31-positive microvascular densities obtained by morphometric analysis of LLC tumors. Each value represents the mean number of vessels ± SD in 5 fields. *P < 0.01 versus LLC/IL-1β. (C) Infiltration of macrophages stained with mAb F4/80 in LLC/neo and LLC/IL-1β tumors. Magnification, ×200. (D) Quantification of the number of macrophages infiltrating LLC/IL-1β and LLC/neo tumors. Magnification, ×400. Each value represents the mean number of macrophages ± SD in 5 microscopic fields. *P < 0.01 versus LLC/IL-1β in wild-type mice using the Mann-Whitney U test.
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