Proangiogenic function of CD40 ligand-CD40 interactions.
Angiogenesis is a characteristic component of cell-mediated immune inflammation. However, little is known of the immunologic mediators of angiogenesis factor production. Interactions between CD40 ligand (CD40L) and CD40 have been shown to have pluripotent functions in inflammation, including the production of cytokines, chemokines, as well as the angiogenesis factor, vascular endothelial growth factor (VEGF), by endothelial cells. In this study we found that treatment of cultured human endothelial cells with an anti-CD40 Ab (to ligate CD40) resulted in the expression of several other angiogenesis factors, including fibroblast growth factor-2 and the receptors Flt-1 and Flt-4. To determine the proangiogenic effect of CD40L in vivo, human skin was allowed to engraft on SCID mice for 6 wk. These healed human skins express CD40 on resident endothelial cells and monocyte/macrophages, but not on CD20-expressing B cells. Skins were injected with saline, untransfected murine fibroblasts, or murine fibroblasts stably transfected with human CD40L. We found that the injection of CD40L-expressing cells, but not control cells, resulted in the in vivo expression of several angiogenesis factors (including VEGF and fibroblast growth factor) and a marked angiogenesis reaction. Mice treated with anti-VEGF failed to elicit an angiogenesis reaction in response to injection of CD40L-expressing cells, suggesting that the proangiogenic effect of CD40L in vivo is VEGF dependent. These observations imply that ligation of CD40 at a peripheral inflammatory site is of pathophysiological importance as a mediator of both angiogenesis and inflammation.
Reinders
Marlies E J
ME
Department of Medicine, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Sho
Masayuki
M
Robertson
Stuart W
SW
Geehan
Christopher S
CS
Briscoe
David M
DM
D000279:Administration, Cutaneous; D043925:Angiogenesis Inducing Agents / Q000096:biosynthesis; D000818:Animals; D019013:CD40 Antigens / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D023201:CD40 Ligand / Q000008:administration & dosage / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D002465:Cell Movement / Q000276:immunology; D016228:Endothelial Growth Factors / Q000502:physiology; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology; D008222:Lymphokines / Q000502:physiology; D051379:Mice; D016513:Mice, SCID; D018448:Models, Immunological; D018919:Neovascularization, Physiologic / Q000276:immunology*; D012333:RNA, Messenger / Q000096:biosynthesis; D016038:Skin Transplantation / Q000276:immunology; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis / Q000235:genetics; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000096:biosynthesis / Q000235:genetics; D042442:Vascular Endothelial Growth Factors
D043925:Angiogenesis Inducing Agents; D019013:CD40 Antigens; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; D023201:CD40 Ligand; D040281:Vascular Endothelial Growth Factor Receptor-1; D040321:Vascular Endothelial Growth Factor Receptor-3