Stimulation of primary human endothelial cell proliferation by IFN.

Abstract

The IFN family of cytokines has pleiotropic roles in immunity and development. In this study, we provide evidence that IFN can stimulate the proliferation of primary human endothelial cells. This is in contrast to the growth-suppressive effects of IFN observed on transformed human cells, thereby underscoring the distinctive responses of primary human cells. The growth-stimulatory effect of IFN was determined by an increase in DNA synthesis assessed with [(3)H]thymidine incorporation, an increase in G(2) and M cell cycle phases assessed with flow cytometric analysis, and an increase in cell number. Distinct cell types, including primary human fibroblast and smooth muscle cells, were also growth stimulated by IFN. Neutralizing Abs to IFN were used to demonstrate the growth response was mediated specifically by the IFN cytokine. The signaling pathway of type I IFNs activates STAT1 and STAT2. In primary endothelial cells, we demonstrate that STAT3 and STAT5 are also activated, and these STATs may contribute to cellular proliferation. To evaluate possible effectors of positive growth, DNA microarray analyses were performed to assess gene induction in response to IFN. These results reveal changes in the RNA levels of genes in endothelial cells that encode proteins involved in cellular proliferation.