Interleukin-1β regulates angiopoietin-1 expression in human endothelial cells

• Published in: Cancer research (Chicago, Ill.) Vol. 64; no. 9; pp. 3186 - 3190
• Main Authors: FAN FAN, STOELTZING, Oliver, WENBIAO LIU, MCCARTY, Marya F, JUNG, Young D, REINMUTH, Niels, ELLIS, Lee M
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.05.2004
• Subjects: Antineoplastic agents; Biological and medical sciences; Medical sciences; Pharmacology. Drug treatments; Tumors; Human; Endothelial cell; Regulation(control); Angiopoietin 1; Cytokine; Interleukin 1β; Gene expression
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-03-0407

Abstract 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-1β (IL-1β), tumor necrosis factor-α, platelet-derived growth factor-BB, insulin-like growth factor-1, or vascular endothelial growth factor (VEGF). Both IL-1β and tumor necrosis factor-α 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-1β down-regulation of Ang-1. Furthermore, treatment of cells with IL-1β indirectly (via down-regulation of Ang-1) led to a decrease in Tie-2 autophosphorylation levels in HUVECs. We previously demonstrated that IL-1β 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-1β would also down-regulate Ang-1 in human vascular smooth muscle cells. Similar to our findings in HUVECs, we found that IL-1β decreased Ang-1 expression in human vascular smooth muscle cells. Direct effects of IL-1β on angiogenesis were investigated by use of an in vivo Gelfoam angiogenesis assay in which IL-1β produced a significant increase in vessel counts (P = 0.0189). These results suggest that IL-1β indirectly regulates angiogenesis by modulating the expression of Ang-1. IL-1β may trigger a proangiogenic response by decreasing Ang-1 levels in ECs and pericytes and up-regulating VEGF in ECs and tumor cells.