Infiltration of COX-2-expressing macrophages is a prerequisite for IL-1 beta-induced neovascularization and tumor growth.
Inflammatory angiogenesis is a critical process in tumor progression and other diseases. The inflammatory cytokine IL-1beta promotes angiogenesis, tumor growth, and metastasis, but its mechanisms remain unclear. We examined the association between IL-1beta-induced angiogenesis and cell inflammation. IL-1beta 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-1beta- 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-1beta-induced angiogenesis and partially inhibited VEGF-induced angiogenesis. Infiltrating macrophages near the IL-1beta-induced neovasculature were COX-2 positive. Lewis lung carcinoma cells expressing IL-1beta (LLC/IL-1beta) 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-1beta. Thus, macrophage involvement might be a prerequisite for IL-1beta-induced neovascularization and tumor progression.
Nakao
Shintaro
S
Department of Medical Biochemistry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Kuwano
Takashi
T
Tsutsumi-Miyahara
Chikako
C
Ueda
Shu-ichi
S
Kimura
Yusuke N
YN
Hamano
Shinjiro
S
Sonoda
Koh-hei
KH
Saijo
Yasuo
Y
Nukiwa
Toshihiro
T
Strieter
Robert M
RM
Ishibashi
Tatsuro
T
Kuwano
Michihiko
M
Ono
Mayumi
M
D000818:Animals; D002465:Cell Movement / Q000502:physiology; D018932:Chemokine CCL2 / Q000172:deficiency / Q000235:genetics; D003315:Cornea / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics*; D007375:Interleukin-1 / Q000502:physiology*; D008264:Macrophages / Q000201:enzymology* / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009369:Neoplasms / Q000201:enzymology* / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D007375:Interleukin-1; D042461:Vascular Endothelial Growth Factor A; D051546:Cyclooxygenase 2