A Cytokine Reborn?

Abstract

Since the first identification of a vasoconstrictor activity present in endothelial cell supernatants (1) and the subsequent isolation of endothelin (ET)-1 in 1988 (2), there has been tremendous interest in the biology of endothelins. In addition to ET-1, further studies have demonstrated the existence of two other endothelins, ET-2 and ET-3, which differ from ET-1 with two and six amino acid residues, respectively (3). The family of endothelins has been an object of intensive research for scientists from many disciplines. The majority of research has focused on the cardiovascular system (for review see References 4 and 5), but there has also been a significant accumulation of data indicating the mediator role of endothelins in a variety of lung disorders (for further review see References 6 and 7). However, despite intense investigation and the identification of ET-1 expression under a number of pathologic conditions related to the lungs, such as pulmonary vascular disease, asthma, and pulmonary fibrosis, a direct link between ET-1 activity and a disease state has been elusive. This Perspective will focus on aspects of endothelin biology that pertain to the pulmonary system. Endothelins are synthesized from precursors known as preproendothelins (ppET), comprising 212 amino acid residues. The large precursors undergo an intermediate cleavage by endopeptidases to form the 38-amino-acid biologically inactive proendothelins, also called big endothelins. Endothelin-converting enzymes are membrane-bound metalloendopeptidases that further cleave proendothelins. The biologically active endothelins are 21-amino-acid peptides, with two disulfide bridges joining cysteins in positions 1-15 and 3-11 in the N-terminal half, and a cluster of hydrophobic amino acid residues at the C-terminal end of the structure. The structure of the N-terminal domain determines the affinity to the receptor, while the C-terminal domain contains the binding site of the peptide to the receptor (for review see Reference 8).Most tissues contain more ET-1 than ET-2 or ET-3, with the highest levels of ET-1 found in lung. ET-1 is secreted by endothelial cells (2, 9), epithelial cells (10, 11), alveolar macrophages (12, 13), polymorphonuclear leukocytes (14), and fibroblasts (15). Release of endothelins is (

Nur77 attenuates endothelin-1 expression via downregulation of NF-κB and p38 MAPK in A549 cells and in an ARDS rat model

“…ET-1 is one of the inflammatory mediators in the pathogenesis of ARDS (18, 77, 81). ET-1 induces TNF-α, IL-1, IL-6, MCP-1, and VCAM-1 production in macrophages, monocytes (3, 23, 85), mast cells (45), and human tracheal smooth muscle cells (38).…”

A Novel Role of Endothelin-1 in Linking Toll-like Receptor 7-mediated Inflammation to Fibrosis in Congenital Heart Block

“…In humans, ET-1 is normally produced by endothelial cells but is also expressed by epithelial cells, bone marrow mast cells, macrophages, polymorphonuclear leukocytes, cardiomyocytes, and fibroblasts (15,41). In the CHB model, ET-1 is secreted by the infiltrating macrophages.…”

“…Of the three isoforms of ET, ET-1 is the significant isoform in humans. ET-1 is initially generated as a precursor of 212 amino acids, which is twice cleaved to a biologically active peptide of 21 amino acids (15). Of potential relevance to the pathogenesis of anti-SSA/Ro-SSB/La-associated cardiac diseases, several lines of evidence support a profibrotic involvement of ET-1 in heart diseases.…”

Neuroinflammation and Infection: Molecular Mechanisms Associated with Dysfunction of Neurovascular Unit

“…Although ET-1 is mainly a vasoconstrictor, it also acts as a pro-inflammatory cytokine, stimulates the aggregation of platelets and induces the expression of leukocyte adhesion molecules. ET-1 also stimulates the synthesis of inflammatory mediators that cause vascular dysfunction and lead to the progression of diseases and inflammation (Teder and Noble, 2000). Several infectious diseases such as malaria (Dai et al, 2012), infection of Rickettsia conorii (Davi et al, 1995), and Chagas disease (Petkova et al, 2001) are associated with ET-1 hyper-expression.…”