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

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

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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The effect of anti-CXCR2 Ab on IL-1β–induced angiogenesis. Kinetics of p...
The effect of anti-CXCR2 Ab on IL-1β–induced angiogenesis. Kinetics of protein expression for (A) VEGF-A, (B) KC (mouse CXCL1), and (C) MIP-2 (mouse CXCL2/3) after IL-1β pellet implantation. Four corneal lysates were prepared and assayed by ELISA on the indicated days (n = 3). *P < 0.01 versus untreated. (D) Expression of ENA-78 (CXCL5) mRNA levels in IL-1β–treated corneas. Six IL-1β–implanted corneas (IL-1β) or untreated corneas (N) were harvested, and real-time RT-PCR was performed to determine ENA-78 (CXCL5) mRNA levels on day 2. Expression was normalized to GAPDH mRNA levels. *P < 0.01 versus untreated. (E) Corneal neovascularization on days 2, 4, and 6 in BALB/c mice with or without i.p. administration of anti-mouse CXCR2 Ab. (F) Quantitative analysis of neovascularization on day 6. IL-1β–induced corneal neovascularization in mice (n = 6) receiving anti-mouse CXCR2 Ab was inhibited compared with mice (n = 6) receiving control goat serum. **P < 0.05 using Student’s t test. (G and H) Comparison of levels of VEGF-A (G) and KC (H) in IL-1β–implanted corneas with or without DFU. On day 4, corneal lysates were prepared from 4 IL-1β–implanted corneas from DFU-treated and untreated mice and individually assayed by ELISA for VEGF-A or KC (n = 3). **P < 0.05 using Student’s t test.