Abstract
Endothelin 1 (ET-1), mainly produced from vascular endothelial cells, induces vasoconstriction in physiological conditions. The endothelin receptor antagonist is among the most effective agents for pulmonary hypertension. However, little is known about the production source of ET-1 in inflammation and immunity. Here, we studied whether T cell-mediated ET-1 production system exists and operates independent of the production system in vascular endothelial cells. ET-1 production was readily detectable in the culture supernatant of human PBMCs and murine spleen cells stimulated with anti-CD3 antibody. Immunocytostaining showed that ET-1-producing cells emerged only in PBMCs stimulated with anti-CD3 antibody. Using the Transwell system, both murine and human monocytes sorted with magnetic beads in the inner chamber produced ET-1 when T cells were activated with antigen or anti-CD3 antibody in the outer chamber. This ET-1 production was inhibited by anti-IFN-γ and/or TNF-α antibody. Furthermore, monocytes purified from ETflox/flox;Tie2-Cre( + ) mice, which conditionally lack ET-1 in hematopoietic stem cells and vascular endothelial cells, did not produce ET-1 even when stimulated by antigen-specific T cell activation. This study demonstrates the existence of an immune-mediated ET-1 production induced by T cells upon activation through IFN-γ and TNF-α.
Highlights
A prominent role for the endothelin (ET) system in the physiological regulation of blood pressure has been long recognized[1]
This human in vitro study clearly showed that peripheral blood mononuclear cells (PBMCs), independent of vascular endothelial cells, produced Endothelin 1 (ET-1) in a manner that was dependent only on the activation of T cells (Fig. 1b)
With the implementation of endothelin receptor antagonist in experimental studies, the blockade of ET-1 mediated signaling with endothelin receptor antagonists reduces the level of inflammation in some animal models of LPS-induced lung inflammation[5], allograft rejection[6], antigen-induced arthritis[7,8], antigen-induced allergic rhinitis[10] and monocrotaline-induced pulmonary artery hypertension[11]
Summary
A prominent role for the endothelin (ET) system in the physiological regulation of blood pressure has been long recognized[1]. Endothelin 1 (ET-1) is a major factor that induces vasoconstriction and is mainly produced by vascular endothelial cells, the primary source of ET-1 in physiological conditions[1,2]. Binding of ET-1 to the endothelin type A receptor (ETa) results in vasoconstriction, growth, and remodeling effects[1,3]. The ET-1 production system has been well investigated in normal physiology in vascular endothelial cells, whether a specific ET-1 production system works in inflammatory conditions remains to be determined. Immune-mediated ET-1 producing system other than LPS-triggering ET-1 production remains to be determined. For this reason, we postulate the possible relationship between T cells and ET-1 producing cells in an immune-mediated ET-1 production system. We explored the existence of an ET-1 production and induction system that is related to the immune system, and demonstrate a newly discovered T cell-mediated vascular endothelial cell-independent ET-1 production system by using human and murine immune cells
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