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Interleukin-1ß Regulates Angiopoietin-1 Expression in Human Endothelial Cells

¹ Departments of Cancer Biology and ² Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

Angiopoietin (Ang)-1 is an important regulator of endothelial cell (EC) survival and stabilization. Ang-1 exerts its biological effects by binding to the EC-specific tyrosine kinase receptor Tie-2, and initiates intracellular signaling in ECs. However, regulatory mechanisms for endothelial Ang-1 expression have not been completely elucidated. In this study, we investigated the effects of angiogenic cytokines and growth factors on Ang-1 expression in human umbilical vein ECs (HUVECs). Northern blot analysis was performed after HUVECs were exposed to interleukin-1ß (IL-1ß), tumor necrosis factor-, platelet-derived growth factor-BB, insulin-like growth factor-1, or vascular endothelial growth factor (VEGF). Both IL-1ß and tumor necrosis factor- caused marked down-regulation of Ang-1 mRNA levels at 4 h with a further decrease observed at 24 h. Using signaling inhibitors, we identified the P38 pathway as the pathway that mediates IL-1ß down-regulation of Ang-1. Furthermore, treatment of cells with IL-1ß indirectly (via down-regulation of Ang-1) led to a decrease in Tie-2 autophosphorylation levels in HUVECs. We previously demonstrated that IL-1ß regulates VEGF expression in tumor cells. This observation was confirmed in ECs in the present study. Because pericytes play a role in regulating EC function, we also determined whether IL-1ß would also down-regulate Ang-1 in human vascular smooth muscle cells. Similar to our findings in HUVECs, we found that IL-1ß decreased Ang-1 expression in human vascular smooth muscle cells. Direct effects of IL-1ß on angiogenesis were investigated by use of an in vivo Gelfoam angiogenesis assay in which IL-1ß produced a significant increase in vessel counts (P = 0.0189). These results suggest that IL-1ß indirectly regulates angiogenesis by modulating the expression of Ang-1. IL-1ß may trigger a proangiogenic response by decreasing Ang-1 levels in ECs and pericytes and up-regulating VEGF in ECs and tumor cells.

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