Gene Expression of Endothelin-1 (Et-1) and Release of Mature Peptide by Activated Human Neutrophils

Cambiaggi, Caterina; Mencarelli, Marzia; Muscettola, Michela; Grasso, Giovanni

doi:10.1006/cyto.2001.0865

Cited by 14 publications

(12 citation statements)

References 13 publications

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“…In the CHB model, ET-1 is secreted by the infiltrating macrophages. The levels of ET-1 secreted by human macrophages approximate those reported for other immune cells, including canine macrophages (42), human dendritic cells (14), and human neutrophils (43). Previous publications support the notion that activation of macrophages induces ET-1 production and release.…”

Section: Discussionsupporting

confidence: 66%

“…Specifically, it was recently reported that the canine macrophage cell line, DH82, constitutively secretes both ET-1 and its biologically inactive precursor big ET-1 and that the production of both peptides is increased after either stimulation with LPS from Gram-negative bacteria or with intact and viable Gram-positive and Gramnegative bacteria (42). The secretion of ET-1 by polymorphonuclear neutrophils, macrophages, and mast cells increases during inflammation (43,44). Down-regulation of ET-1 mRNA expression and protein secretion by macrophages treated with either hY3 or IC in the presence of IRS661, a specific antagonist of TLR7, indicates that elevated ET-1 expression is TLR7-dependent.…”

Section: Discussionmentioning

confidence: 99%

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

Álvarez

Briassouli

Clancy

et al. 2011

Journal of Biological Chemistry

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Autoimmune associated congenital heart block (CHB) may result from pathogenic cross-talk between inflammatory and profibrosing pathways. Incubation of macrophages with immune complexes (IC) composed of Ro60, a target of the pathologic maternal autoantibodies necessary for CHB, hY3 ssRNA, and affinity-purified anti-Ro60 antibody induces the Toll-like receptor 7 (TLR7)-dependent generation of supernatants that provoke a fibrosing phenotype in human fetal cardiac fibroblasts. We show herein that these cells are a major source of TGF␤ and that endothelin-1 (ET-1) is one of the key components responsible for the profibrosing effects generated by stimulated macrophages. Supernatants from macrophages incubated with IC induced the fibroblast secretion of TGF␤, which was inhibited by treating the macrophages with an antagonist of TLR7. Under the same conditions, the induced fibroblast secretion of TGF␤ was decreased by inhibitors of the ET-1 receptors ETa or ETb or by an anti-ET-1 antibody but not by an isotype control. Exogenous ET-1 induced a profibrosing phenotype, whereas fibroblasts transfected with either ETa or ETb siRNA were unresponsive to the profibrosing effects of the IC-generated macrophage supernatants. Immunohistochemistry of the hearts from two fetuses dying with CHB revealed the presence of ET-1-producing mononuclear cells in the septal region in areas of calcification and fibrosis. In conclusion, these data support a novel role of ET-1 in linking TLR7 inflammatory signaling to subsequent fibrosis and provide new insight in considering therapeutics for CHB.Cardiac conduction defects detected before or at birth, in the absence of structural abnormalities, are strongly associated with maternal autoantibodies to SSA/Ro and/or SSB/La ribonucleoproteins, independent of whether the mother has systemic lupus erythematosus or Sjögren's syndrome or is asymptomatic (1, 2). The mechanism by which maternal anti-SSA/ Ro-SSB/La antibodies initiate and perpetuate inflammation with consequent scarring of the atrioventricular node (the signature lesion of CHB) 2 and endocardium (3) has not been fully defined. One proposed pathologic cascade centers apoptosis of the fetal cardiocytes as the cellular event that accounts for the surface expression of the otherwise intracellular target antigens (4 -6), facilitating subsequent opsonization by circulating maternal autoantibodies. Experimental data suggest that hY3 ssRNA associated with the SSA/Ro protein bound by affinitypurified anti-Ro60 antibody (AP60) gains access to the macrophage endosome via Fc␥R uptake with subsequent ligation of the Toll-like receptor 7 (TLR7). In clearing the opsonized apoptotic cardiomyocytes, infiltrating macrophages secrete factors that promote a scarring phenotype of the resident cardiac fibroblasts, as evidenced by their transdifferentiation to myofibroblasts and production of collagen (7,8).Immunohistochemical studies (5) of hearts from several fetuses dying with CHB demonstrate abundant TGF␤ in the septal region. TGF␤ probably contributes to s...

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Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

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

Álvarez

Briassouli

Clancy

et al. 2011

Journal of Biological Chemistry

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“…Increased plasma concentration of ET-1 in hemorrhagic patients was observed in the early phase (2-3 days) following SAH only [51]. Activated leukocytes produce ET-1, and additionally they express endothelin receptor that may form a potential link between inflammatory cells and their vascular target [52,53].…”

Section: Discussionmentioning

confidence: 99%

Interleukin-1&bgr; Increases Release of Endothelin-1 and Tumor Necrosis Factor as Well as Reactive Oxygen Species by Peripheral Leukocytes During Experimental Subarachnoid Hemorrhage

Larysz‐Brysz

Lewin–Kowalik²,

Czuba³

et al. 2012

CNR

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In the subarachnoid hemorrhage (SAH) blood mixes with cerebrospinal fluid, what starts immunoinflammatory processes - increased synthesis of proinflammatory cytokines, and formation of reactive oxygen species (ROS), resulting in pre-activation of different populations of peripheral leukocytes. Migration of leukocytes to the brain parenchyma through broken blood brain barrier may produce extra brain tissue injury besides of that resulting from SAH. We examined in adult rats the effect of interleukin-1β (IL-1β) neutralization on secretion of cytokines as well as production of ROS in the course of SAH. SAH was produced by injection of 150 μL of autologous arterial blood into cisterna magna. In 50% of animals, IL-1beta activity was inhibited by intracerebroventricular administration of anti-rat IL-1β antibodies. Ninety minutes or 24 hrs following surgery, blood samples were drawn from the extraorbital plexus and centrifuged to obtain two leukocyte subpopulations - polymorphonuclear (PMN) and mononuclear (MN). The chemiluminescence, a hallmark of ROS synthesis, was measured in PMNs. In supernatants from MNs cultures, concentrations endothelin-1 (ET-1), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were assessed. SAH caused the increase ofn PMNs chemiluminescence as well as the increase of production of ET-1 and TNF-α by MNs but had no influence on IL-6 concentration. Neutralization of IL-1β resulted in significant decrease of chemiluminescence as well as concentration of both ET-1 and TNF-α, while IL-6 concentration was increased. These revealed an important role of IL-1β in the activation of peripheral leukocytes in the course of subarachnoid hemorrhage.

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“…8 Activation of vascular ET-1 production is associated with hypertrophic remodeling of resistance arteries. 9,10 The local production of ET-1 may induce inflammation, [11][12] which is increasingly recognized as participating in the pathogenesis of cardiovascular disease. There are several known relationships between aldosterone and ET-1.…”

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confidence: 99%

Endothelin Antagonism on Aldosterone-Induced Oxidative Stress and Vascular Remodeling

et al. 2003

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Abstract-Endothelin A (ET A ) receptor blockade has prevented vascular remodeling in aldosterone and salt-induced hypertension. To evaluate effects of the ET A receptor antagonist, BMS 182874, compared with the aldosterone antagonist, spironolactone, on vascular remodeling in aldosterone-infused rats not exposed to a high salt diet, Sprague-Dawley rats were infused subcutaneously with aldosterone (0.75 g/h) and treated with BMS 182874 (40 mg · kg, spironolactone, or hydralazine (both 25 mg · kg Ϫ1 · d Ϫ1 ) while receiving a normal salt diet for 6 weeks. Aldosterone increased systolic BP (PϽ0.01), plasma endothelin (3.33Ϯ0.32 versus 1.85Ϯ0.40 pmol/L in control, PϽ0.05), systemic oxidative stress as shown by plasma thiobarbituric acid-reacting substances and vascular nicotinamide adenine dinucleotide phosphate (NADPH) activity. Aldosterone increased small artery media thickness (17.7Ϯ0.9 versus 13.6Ϯ0.8 m in control, PϽ0.05) and media/lumen ratio (7.6Ϯ0.4 versus 5.5Ϯ0.4% in control, PϽ0.05), with growth index of 21% indicating hypertrophic remodeling. Laser confocal microscopy showed increased collagen and fibronectin deposition and intercellular adhesion molecule-1 (ICAM-1) content in the vessel wall of aldosterone-infused rats. The 3 treatments lowered BP, although hydralazine was slightly less effective. BMS 182874 and spironolactone decreased oxidative stress, normalized the hypertrophic remodeling, decreased collagen and fibronectin deposition, and reduced ICAM-1 abundance in the vascular wall of aldosterone-infused rats, whereas hydralazine only reduced NADPH activity in aorta but did not affect the remaining parameters. Vascular remodeling of small arteries occurs in aldosterone-infused rats exposed to a normal salt diet and may be mediated in part by ET-1 via stimulation of ET A receptors. Endothelin blockade may exert beneficial effects on vascular remodeling, fibrosis, oxidative stress, and adhesion molecule expression in aldosterone-induced hypertension.

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Gene Expression of Endothelin-1 (Et-1) and Release of Mature Peptide by Activated Human Neutrophils

Cited by 14 publications

References 13 publications

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

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

Interleukin-1&bgr; Increases Release of Endothelin-1 and Tumor Necrosis Factor as Well as Reactive Oxygen Species by Peripheral Leukocytes During Experimental Subarachnoid Hemorrhage

Endothelin Antagonism on Aldosterone-Induced Oxidative Stress and Vascular Remodeling

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