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.
View: Text | PDF
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

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

×

Figure 4

Options: View larger image (or click on image) Download as PowerPoint
The effect of Cl2MDP-LIPs on IL-1β–induced angiogenesis. (A) FACS analys...
The effect of Cl2MDP-LIPs on IL-1β–induced angiogenesis. (A) FACS analysis of infiltrating cells on day 6, in IL-1β–implanted corneas from BALB/c mice that received Cl2MDP-LIPs or PBS-LIPs i.v. and/or s.c. The cells were stained with PE-CD11b mAb and FITC–Gr-1 or FITC-F4/80 mAb. (B) Corneal neovascularization at the indicated time points in BALB/c mice receiving Cl2MDP-LIPs or PBS-LIPs i.v. and/or s.c. The percentages of infiltrating cells in IL-1β–implanted corneas of Cl2MDP-LIP– or PBS-LIP–treated mice were 4.75% ± 0.48% (i.v., CD11b+F4/80+), 13.2% ± 4.03% (i.v., CD11b+Gr-1+), 1.63% ± 0.30% (i.v. + s.c., CD11b+F4/80+), and 6.61% ± 0.93% (i.v. + s.c., CD11b+Gr-1+). (C) Neovascularization was quantified by area in mm2 on day 4 (white bars) and day 6 (black bars). Bars show means ± SD of independent experiments (n = 3 or 4; *P < 0.01 and **P < 0.05 versus PBS-LIPs). (D) Corneal neovascularization induced with VEGF at the indicated time points after receiving Cl2MDP-LIPs or PBS-LIPs (i.v. + s.c.). (E) Quantitative analysis of neovascularization on day 6. VEGF-induced corneal neovascularization in mice (n = 6) receiving Cl2MDP-LIPs was inhibited compared with mice (n = 6) receiving PBS-LIPs. *P < 0.01 using the Student’s t test.