Interferon-alpha and interleukin 2 synergistically enhance basic fibroblast growth factor synthesis and induce release, promoting endothelial cell growth.
To elucidate mechanisms underlying neovascularization that accompanies certain chronic immune/inflammatory disorders, the effects of interferon-alpha (IFN-alpha) and interleukin 2 (IL-2) on endothelial cell (EC) growth in vitro and angiogenesis in vivo were studied. Preincubation of cultured human ECs with IFN-alpha, followed by exposure to IL-2, resulted in effective stimulation of cell growth, whereas either cytokine alone had only a slight effect. The combination of IFN-alpha/IL-2 induced an angiogenic response in the rabbit cornea. IL-2 receptor expression was enhanced on IFN-alpha-treated ECs: p55 was increased and p70 was induced. 125I-IL-2 binding to ECs treated with IFN-alpha was enhanced (Kd from approximately 7 nM to approximately 260 pM with IFN-alpha), and anti-p55 IgG blocked 125I-IL-2/EC interaction as well as IL-2-mediated EC proliferation. Consistent with these findings in cell culture, immunohistologic studies demonstrated p55 and p70 antigen in the vasculature of rheumatoid joints, but not in normal joint tissue. Exposure of cultured ECs to IFN-alpha increased levels of intracellular EC basic fibroblast growth factor (bFGF), and subsequent addition of IL-2 led to bFGF release into the medium. The observation that anti-bFGF IgG largely blocked EC proliferation in response to IFN-alpha/IL-2 suggested that bFGF was a critical agent in this setting. These data suggest a mechanism rendering ECs responsive to IL-2 which may be relevant in immune/inflammatory disorders: IFN-alpha-mediated induction of functional EC receptors for IL-2, which drives cell proliferation by a mechanism dependent on increased synthesis and release of bFGF.
Cozzolino
F
F
Dipartimento di Medicina Sperimentale e Scienze Biochimiche, University of Rome Tor Vergata, Italy.
Torcia
M
M
Lucibello
M
M
Morbidelli
L
L
Ziche
M
M
Platt
J
J
Fabiani
S
S
Brett
J
J
Stern
D
D
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000473:pathology; D002455:Cell Division; D002478:Cells, Cultured; D003315:Cornea / Q000098:blood supply; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000254:growth & development; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis* / Q000494:pharmacology; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology*; D007596:Joints / Q000473:pathology; D009389:Neovascularization, Pathologic; D011817:Rabbits; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology
D016898:Interferon-alpha; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D016222:Fibroblast Growth Factor 2