The activity of soluble VCAM-1 in angiogenesis stimulated by IL-4 and IL-13.
IL-13 is a multifunctional lymphokine sharing a number of biological properties with IL-4. We previously observed that IL-4 shows angiogenic activities in vitro as well as in vivo. In this study we examined the effect of IL-13 on angiogenesis in vitro and in vivo and also the underlying mechanisms. Human IL-13 significantly stimulated the formation of tube-like structures in collagen gels by human microvascular endothelial cells and bovine aortic endothelial cells by about 3-fold over the controls in the absence of the cytokines. Administration of murine IL-13 led to neovascularization when implanted in the rat cornea. Coadministration of neutralizing mAb to the IL-4R inhibited both tubular morphogenesis in vitro and activation of STAT6 induced by IL-4 or IL-13. Both IL-4 and IL-13 markedly increased mRNA levels of VCAM-1 in vascular endothelial cells, and the production of the soluble form of VCAM-1 was also stimulated in response to IL-4 or IL-13. Administration of anti-VCAM-1 Ab in vitro blocked tubular morphogenesis induced by IL-4 and IL-13. Angiogenesis induced in vivo in rat cornea by IL-4 and IL-13 was also inhibited by Ab against the rat alpha4 integrin subunit. These findings suggest that angiogenesis dependent on IL-4 and IL-13 is mainly mediated through a soluble VCAM-1/alpha4 integrin pathway.
Fukushi
J
J
Department of Medical Biochemistry, Graduate School of Medical Sciences, Kyushu University, Maidashi, Higashi-ku, Fukuoka, Japan. fukushi@mailserver.med.kyushu-u.ac.jp
Ono
M
M
Morikawa
W
W
Iwamoto
Y
Y
Kuwano
M
M
D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D003315:Cornea / Q000098:blood supply / Q000276:immunology; D016510:Corneal Neovascularization / Q000276:immunology / Q000517:prevention & control; D004343:Drug Implants; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007106:Immune Sera / Q000494:pharmacology; D039441:Integrin alpha4; D018793:Interleukin-13 / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000502:physiology*; D015847:Interleukin-4 / Q000502:physiology*; D008297:Male; D008833:Microcirculation / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000276:immunology*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D019948:Receptors, Interleukin-4 / Q000276:immunology; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000276:immunology; D012995:Solubility; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism*
D015703:Antigens, CD; D004343:Drug Implants; D007106:Immune Sera; D018793:Interleukin-13; D019948:Receptors, Interleukin-4; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015534:Trans-Activators; D019010:Vascular Cell Adhesion Molecule-1; D039441:Integrin alpha4; D015847:Interleukin-4