Stimulation of primary human endothelial cell proliferation by IFN.
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.
Gomez
Dolores
D
Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA.
Reich
Nancy C
NC
D000818:Animals; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D020405:Dermis / Q000166:cytology; D004730:Endothelium, Vascular / Q000166:cytology* / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D004789:Enzyme Activation / Q000276:immunology; D005347:Fibroblasts / Q000166:cytology / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D006131:Growth Inhibitors / Q000494:pharmacology; D006133:Growth Substances / Q000494:pharmacology*; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology*; D016898:Interferon-alpha; D051379:Mice; D008807:Mice, Inbred BALB C; D008894:Milk Proteins; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology; D010766:Phosphorylation; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D015534:Trans-Activators / Q000378:metabolism; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism; D014470:Umbilical Cord / Q000166:cytology; D048051:p38 Mitogen-Activated Protein Kinases
D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; D006133:Growth Substances; D007370:Interferon Type I; D016898:Interferon-alpha; D008894:Milk Proteins; D016328:NF-kappa B; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D015534:Trans-Activators; C080665:interferon-alpha A-D; D014443:Tyrosine; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases