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

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

Research output: Contribution to journalArticlepeer-review

218 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2979-2991
Number of pages13
JournalJournal of Clinical Investigation
Volume115
Issue number11
DOIs
Publication statusPublished - Nov 2005

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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