p38 mitogen-activated protein kinase contributes to TNFα-induced endothelial tube formation of bone-marrow-derived mesenchymal stem cells by activating the JAK/STAT/TIE2 signaling axis

Bone marrow-derived mesenchymal stem cells (BM-MSCs) can differentiate into endothelial cells in an inflammatory microenvironment.However, the regulatory mechanisms underlying this process are not entirely understood.Here, we found that TIE2 in BM-MSCs was upregulated at the transcriptional level after stimulation with tumor necrosis factor-alpha (TNFα), a major pro-inflammatory cytokine.Additionally, the STAT-binding sequence within the proximal region of TIE2 was necessary for TNFα-induced TIE2 promoter activation.TIE2 and STAT3 knockdown reduced TNFα-induced endothelial tube formation in BM-MSCs.Among the major TNFα-activated MAP kinases (ERK1/2, JNK1/2, and p38 MAPK) in BM-MSCs, only inhibition of the p38 kinase abrogated TNFα-induced TIE2 upregulation by inhibiting the JAK-STAT signaling pathway.These findings suggest that p38 MAP contributes to the endothelial differentiation of BM-MSCs by activating the JAK-STAT-TIE2 signaling axis in the inflammatory microenvironment.