Function and survival of dendritic cells depend on endothelin-1 and endothelin receptor autocrine loops

Guruli, Georgi; Pflug, Beth R.; Pecher, Stefana; Makarenkova, Valeria P.; Shurin, Michael R.; Nelson, Joel B.

doi:10.1182/blood-2003-10-3559

Cited by 59 publications

(46 citation statements)

References 67 publications

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“…ET-1 axis seems to be involved in DC behavior and function. Indeed, these cells produce ET-1 and express functional ET A R and ET B R, which are both highly expressed during DC maturation (11). However, whereas ET A R blockade significantly reduces the expression of CD83 (a marker of mature dendritic cell marker), decreases the production of interleukin-12, and promotes DC apoptosis, ET B R blockade results in increased expression of CD83 and improved DC survival (11).…”

Section: Role Of Et-1 In the Interactions Of Tumor Cells With The Micmentioning

confidence: 99%

Endothelin therapeutics in cancer: Where are we?

Rosanò¹,

Bagnato²

2016

American Journal of Physiology-Regulatory, Integrative and Comp

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In human cancers, the autocrine and paracrine loop mediated by the aberrantly activation of endothelin-1 (ET-1) receptor (ET-1R) elicits pleiotropic effects, preferentially mediated by the scaffold protein ␤-arrestin 1 (␤-arr1), on tumor cells and on the host microenvironment, providing a strong rationale for targeting ET-1 receptors. This review describes the most up-to-date preclinical and clinical results obtained by using ET-1 therapeutics. The previous negative clinical results of ET-1 therapeutics should not prevent us from setting the standard of this class of drugs for future well-designed clinical trials. The preclinical data obtained with the dual ET AR and ETBR antagonist macitentan indicate that this molecule, which targets cancer cells and tumor-associated microenvironmental elements, could be a cancer therapeutic option. The field of ET-1 therapeutics will be improved in the next decade, facilitated by the new knowledge on the genomic landscape of the human stroma and tumor, and by the low invasive approaches based on liquid biopsies for the discovery of predictive biomarkers. The information obtained from preclinical studies in patient-derived models and from the Cancer Genome Atlas will set the scene of precision medicine for cancer. Results from these studies are expected to open the possibility that ET-1R antagonists might be more efficacious as molecular cancer therapeutics, able to hamper the functional ␤-arr1-dependent signaling complexes, either alone or coupled with new targeted approaches.␤-arrestin; cancer; endothelin-1; endothelin-1 receptor; target therapy RECENT INVESTIGATIONS have consistently suggested that endothelin-1 (ET-1), a small bioactive peptide of 21 residues derived from longer prepro-ET-1 precursor, is an important signal messenger in different pathological conditions, including human cancers (24,35). ET-1 belongs to a family of closely related peptides that include ET-2 and ET-3, which are all similar in structure to ET-1, but are separate gene products, with tissue-specific expression. ETs act mainly via G protein-coupled receptors (GPCR) from endothelin receptor type A (ET A R) and B (ET B R) (24). The two receptors can be differentiated by agonists and antagonists binding affinity and in their cellular distributions. The ET A R binds ET-1 with the greatest affinity, whereas ET-1, ET-2, and ET-3 all have equal affinity for the ET B R.It is now well known that ET-1 receptors can activate several signaling pathways in a G protein-independent manner via complexes with ␤-arrestin (␤-arr)-1 or -2 (18, 24). The scaffold protein ␤-arr1 serves as a copilot in ET-1 signaling to organize complex networks driving tumor progression (7,23,25,26,28,30,33). Thus ET-1 axis confers pleiotropic effects on both tumor cells and microenvironment, modulating different processes by activating ␤-arr-mediated pathways (Fig. 1A). A lesson learned from various tumor models is that there are different expression profiles of the ET-1 receptors compared with normal tissues. There are cancers expres...

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Section: Role Of Et-1 In the Interactions Of Tumor Cells With The Micmentioning

confidence: 99%

Endothelin therapeutics in cancer: Where are we?

Rosanò¹,

Bagnato²

2016

American Journal of Physiology-Regulatory, Integrative and Comp

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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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“…Conversely, selective ET-B receptor blockade resulted in increased expression of CD83 and improved DC survival. Therefore, ET-1/ET-A/ET-B autocrine/paracrine loops on DCs appear to be essential for the normal maturation and function of human DCs [27]. How this modifies disease progression in PAH patients taking these drugs is unclear at present.…”

mentioning

confidence: 99%

“…Furthermore, combined endothelin (ET) receptor A and B antagonists (ERAs, e.g. bosentan) also alter the functional properties of DCs [27]. The biological effects of ET-1 are not limited to its potent vasoconstricting activity.…”

mentioning

confidence: 99%