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 inter feron-alpha (IFN-alpha) and interleukin 2 (IL-2) on endothelial cell ( EC) growth in vitro and angiogenesis in vivo were studied. Preincubati on of cultured human ECs with IFN-alpha, followed by exposure to IL-2, resulted in effective stimulation of cell growth, whereas either cyto kine alone had only a slight effect. The combination of IFN-alpha/IL-2 induced an angiogenic response in the rabbit cornea. IL-2 receptor ex pression was enhanced on IFN-alpha-treated ECs: p55 was increased and p70 was induced. I-125-IL-2 binding to ECs treated with IFN-a was enha nced (K(d) from almost-equal-to 7 nM to almost-equal-to 260 pM with IF N-alpha), and anti-p55 IgG blocked I-125-IL-2/EC interaction as well a s IL-2-mediated EC proliferation. Consistent with these findings in ce ll culture, immunohistologic studies demonstrated p55 and p70 antigen in the vasculature of rheumatoid joints, but not in normal joint tissu e. Exposure of cultured ECs to IFN-alpha increased levels of intracell ular EC basic fibroblast growth factor (bFGF), and subsequent addition of IL-2 led to bFGF release into the medium. The observation that ant i-bFGF IgG largely blocked EC proliferation in response to IFN-alpha/I L-2 suggested that bFGF was a critical agent in this setting. These da ta suggest a mechanism rendering ECs responsive to IL-2 which may be r elevant 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.