TLR2 and TLR4 agonists induce production of the vasoactive peptide endothelin-1 by human dendritic cells

Spirig, Rolf; Potapova, Inga; Shaw-Boden, Jane; Tsui, Janice; Rieben, Robert; Shaw, Sidney

doi:10.1016/j.molimm.2009.05.179

Cited by 30 publications

(29 citation statements)

References 31 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: 68%

“…The source of ET-1 is not restricted to endothelial cells. Human macrophages have been shown to produce ET-1 in response to lipopolysaccharide (LPS) (13), and human monocyte-derived dendritic cells secrete ET-1 in response to TLR2 and TLR4 agonists (14). ET-1 acts through the stimulation of two subtypes of receptors, ET-1 receptor subtype A (ETa) and ET-1 receptor subtype B (ETb).…”

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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: 68%

mentioning

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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“…In addition to the above considerations, TLR4 agonists have been found to induce (in human dendritic cells) production of the vasoconstrictive mediator ET-1 (Spirig et al 2009). We have previously shown that ET-1 is an important mediator of I/R-induced FGR (Thaete & Neerhof 2006).…”

Section: Discussionmentioning

confidence: 93%

Impact of toll-like receptor 4 deficiency on the response to uterine ischemia/reperfusion in mice

Thaete

Jilling

et al. 2013

Reproduction

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Our objective was to determine the role of toll-like receptor 4 (TLR4) in uterine ischemia/reperfusion (I/R)-induced fetal growth restriction (FGR). Pregnant TLR4-deficient and wild-type mice were subjected to I/R or a sham procedure. Fetal and placental weights were recorded and tissues were collected. Pep-1 (inhibits low-molecular-weight hyaluronan (LMW-HA) binding to TLR4) was used to determine whether LMW-HA-TLR4 interaction has a role in FGR. TLR4-deficient mice exhibited significantly lower baseline fetal weights compared with wild-type mice (P!0.05), along with extensive placental calcification that was not present in wild-type mice. Following I/R, fetal and placental weights were significantly reduced in wild-type (P!0.05) but not in TLR4-deficient mice. However, I/R increased fetal loss (P!0.05) only in TLR4-deficient mice. Corresponding with the reduced fetal weights, uterine myeloperoxidase activity increased in wild-type mice (P!0.001), indicating an inflammatory response, which was absent in TLR4-deficient mice. TLR4 was shown to have a regulatory role for two anti-inflammatory cytokines: interferon-B1 decreased only in wild-type mice (P!0.01) and interleukin-10 increased only in TLR4-deficient mice (P!0.001), in response to I/R. Pep-1 completely prevented I/R-induced FGR (P!0.001), indicating a potential role for the endogenous TLR4 ligand LMW-HA in I/R-induced FGR. In conclusion, uterine I/R in pregnancy produces FGR that is dependent on TLR4 and endogenous ligand(s), including breakdown products of HA. In addition, TLR4 may play a role in preventing pregnancy loss after uterine I/R.

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“…ET-1 is a 21-amino acid peptide and is expressed by a variety of cell types, including immune cells, endothelial cells, neurons, and glial cells of the central and peripheral nervous systems (20)(21)(22)(23)(24)(25)(26). ET-1 is a potent vasoconstrictor that can also evoke pain sensations in rodents and humans (14,22,(27)(28)(29)(30)(31)(32)(33)(34)(35)(36).…”

Section: Introductionmentioning

confidence: 99%

Neural peptidase endothelin-converting enzyme 1 regulates endothelin 1–induced pruritus

et al. 2014

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In humans, pruritus (itch) is a common but poorly understood symptom in numerous skin and systemic diseases. Endothelin 1 (ET-1) evokes histamine-independent pruritus in mammals through activation of its cognate G protein-coupled receptor endothelin A receptor (ETAR). Here, we have identified neural endothelin-converting enzyme 1 (ECE-1) as a key regulator of ET-1-induced pruritus and neural signaling of itch. We show here that ETAR, ET-1, and ECE-1 are expressed and colocalize in murine dorsal root ganglia (DRG) neurons and human skin nerves. In murine DRG neurons, ET-1 induced internalization of ETAR within ECE-1-containing endosomes. ECE-1 inhibition slowed ETAR recycling yet prolonged ET-1-induced activation of ERK1/2, but not p38. In a murine itch model, ET-1-induced scratching behavior was substantially augmented by pharmacological ECE-1 inhibition and abrogated by treatment with an ERK1/2 inhibitor. Using iontophoresis, we demonstrated that ET-1 is a potent, partially histamine-independent pruritogen in humans. Immunohistochemical evaluation of skin from prurigo nodularis patients confirmed an upregulation of the ET-1/ETAR/ECE-1/ERK1/2 axis in patients with chronic itch. Together, our data identify the neural peptidase ECE-1 as a negative regulator of itch on sensory nerves by directly regulating ET-1-induced pruritus in humans and mice. Furthermore, these results implicate the ET-1/ECE-1/ERK1/2 pathway as a therapeutic target to treat pruritus in humans.

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TLR2 and TLR4 agonists induce production of the vasoactive peptide endothelin-1 by human dendritic cells

Cited by 30 publications

References 31 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

Impact of toll-like receptor 4 deficiency on the response to uterine ischemia/reperfusion in mice

Neural peptidase endothelin-converting enzyme 1 regulates endothelin 1–induced pruritus

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