β-Tryptase up-regulates vascular endothelial growth factor expression via proteinase-activated receptor-2 and mitogen-activated protein kinase pathways in bone marrow stromal cells in acute myeloid leukemia

Abstract

Tryptases are predominantly mast cell-specific serine proteases with pleiotropic biological activities. Recently, significant amounts of tryptases have been shown to be produced by myeloblasts in certain patients with acute myeloid leukemia (AML), but the function of secreted tryptases in pathological circumstances remains unknown. In this study, we investigated whether β-tryptase affects the expression of vascular endothelial growth factor (VEGF) in bone marrow stromal cells (BMSCs) in AML. We detected the expression of proteinase-activated receptor-2 (PAR-2) on AML BMSCs and found that β-tryptase significantly up-regulated VEGF mRNA and protein expression in a dose-dependent manner by real-time PCR, Western blot, and ELISA. Furthermore, β-tryptase increased ERK1/2 and p38MAPK phosphorylation, and pretreatment with FLLSY-NH₂, PD98059, and SB230580 (PAR-2, ERK1/2, and p38MAPK inhibitors, respectively) inhibited the β-tryptase-induced production of VEGF. These results suggest that β-tryptase up-regulates VEGF production in AML BMSCs via the PAR-2, ERK1/2, and p38MAPK signaling pathways.

Keywords:

• AML
• β-tryptase
• VEGF
• PAR-2
• ERK1/2
• P38MAPK

Acknowledgement

We thank Han Wei for skillful technical assistance.

Declaration of interest: This study was supported by grants from the Natural Science Foundation of Liaoning Province (No. 20082117) and the Liaoning Provincial Department of Education (No. 2008782).