Role of protein tyrosine phosphatase 1B (PTP1B) in the increased sensitivity of endothelial cells to a promigratory effect of erythropoietin in an inflammatory environment

Abstract

The proliferation and migration of endothelial cells are vascular events of inflammation, a process which can also potentiate the effects of promigratory factors. With the aim of investigating possible modifications in the activity of erythropoietin (Epo) in an inflammatory environment, we found that Epo at a non-promigratory concentration was capable of stimulating EA.hy926 endothelial cell migration when TNF-α was present. VCAM-1 and ICAM-1 expression, as well as adhesion of monocytic THP-1 cells to endothelial layers were also increased. Structurally modified Epo (carbamylation or N-homocysteinylation) did not exhibit these effects. The sensitizing effect of TNF-α on Epo activity was mediated by the Epo receptor. Inhibition assays targeting the PI3K/mTOR/NF-κB pathway, shared by Epo and TNF-α, show a crosstalk between both cytokines. As observed in assays using antioxidants, cell migration elicited by TNF-α+Epo depended on TNF-α-generated reactive oxygen species (ROS). ROS-mediated inactivation of protein tyrosine phosphatase 1B (PTP1B), involved in Epo signaling termination, could explain the synergistic effect of these cytokines. Our results suggest that ROS generated by inflammation inactivate PTP1B, causing the Epo signal to last longer. This mechanism, along with the cross-talk between both cytokines, could explain the sensitizing action of TNF-α on the migratory effect of Epo.

Erythropoietin: A Personal Alice in Wonderland Trip in the Shadow of the Giants

“…In this regard, the 56KD band identified by M-20 was recently confirmed to represent the EPO-R protein by mass spectrometry by Lamon et al [141]. For its high sensitivity, the antibody C-20 was used to detect EPO-R until recently (see, as an example, [142]).…”

Regenerative Properties of Recombinant Human Erythropoietin in the Wound Healing

“…EPO has a number of functions other than hematopoietic. EPO receptors are found not only on the erythroid elements of the bone marrow but also on the cells of the nervous tissue, ovaries and testes, uterus, vascular smooth muscle cells, cardiomyocytes, endotheliocytes, epithelium of the lungs and renal tubules, and other cells [4]. Considering that EPO receptors are expressed on endothelial cells, macrophages, fibroblasts, mast cells, melanocytes, and hair follicles, it has been suggested that EPO is able to accelerate the regeneration of skin wounds by stimulating angiogenesis, the formation of extracellular matrix and collagen, as well as limiting inflammatory mediators and apoptosis [5], [6], [7], [8].…”