Down-modulation of monocyte transendothelial migration and endothelial adhesion molecule expression by fibroblast growth factor: reversal by the anti-angiogenic agent SU6668.
Basic and acidic fibroblast growth factor (bFGF and aFGF, respectively) and vascular endothelial growth factor (VEGF) exert angiogenic actions and have a role in wound healing, inflammation, and tumor growth. Monocytes and endothelial cells are involved in these processes, but the effect of FGF and VEGF on monocyte-endothelial cell interactions has not been defined. We observed that monocyte adhesion to resting or cytokine (tumor necrosis factor-alpha or interleukin-1 alpha)-stimulated human umbilical vein endothelial cells (HUVECs) was markedly inhibited (40 to 65%) by culture (1 to 6 days) of HUVECs with aFGF or bFGF. Monocyte transendothelial migration induced by C5a and chemokines (MCP-1, SDF-1 alpha, RANTES, MIP-1 alpha) was also suppressed (by 50 to 75%) on bFGF-stimulated HUVECs. VEGF did not have these effects at the concentrations used (10 to 20 ng/ml), although like bFGF, it promoted HUVEC proliferation. Culture of HUVECs with bFGF and aFGF significantly down-regulated intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin expression on resting or tumor necrosis factor-alpha-stimulated HUVECs, but had no influence on platelet endothelial cell adhesion molecule (PECAM)-1 and VE-cadherin expression. bFGF also inhibited MCP-1 production by HUVECs. The inhibitory effects of bFGF on monocyte transendothelial migration and adhesion molecule expression were reversed by SU6668, an anti-angiogenic agent and bFGF receptor tyrosine kinase inhibitor. Our results suggest that bFGF and aFGF may suppress endothelial-dependent monocyte recruitment and thus have an anti-inflammatory action during angiogenesis in chronic inflammation but inhibit the immunoinflammatory tumor defense mechanism. However, SU6668 is an effective agent to prevent this down-regulatory action of bFGF on monocyte-endothelial cell interactions.
Zhang
Hong
H
Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada.
Issekutz
Andrew C
AC
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D015703:Antigens, CD; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion; D002465:Cell Movement; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000378:metabolism; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism; D015936:Complement C5a / Q000378:metabolism; D015536:Down-Regulation; D019040:E-Selectin / Q000378:metabolism; D016228:Endothelial Growth Factors / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D016220:Fibroblast Growth Factor 1 / Q000502:physiology*; D016222:Fibroblast Growth Factor 2 / Q000502:physiology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008222:Lymphokines / Q000502:physiology*; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects; D000078183:Oxindoles; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011422:Propionates; D011758:Pyrroles / Q000494:pharmacology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014945:Wound Healing; D000099152:Cadherin 5
D020533:Angiogenesis Inhibitors; D015703:Antigens, CD; D015820:Cadherins; D018932:Chemokine CCL2; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D015936:Complement C5a; D019040:E-Selectin; D016228:Endothelial Growth Factors; D016220:Fibroblast Growth Factor 1; D016222:Fibroblast Growth Factor 2; D007211:Indoles; D018799:Intercellular Adhesion Molecule-1; D008222:Lymphokines; D019402:Macrophage Inflammatory Proteins; D000078183:Oxindoles; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011422:Propionates; D011758:Pyrroles; D019010:Vascular Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000099152:Cadherin 5; C515255:CXCL12 protein, human; C412603:orantinib