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

Blood ◽  
2004 ◽  
Vol 104 (7) ◽  
pp. 2107-2115 ◽  
Author(s):  
Georgi Guruli ◽  
Beth R. Pflug ◽  
Stefana Pecher ◽  
Valeria Makarenkova ◽  
Michael R. Shurin ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Endothelin Receptors ◽  
Interleukin 12 ◽  
Endothelin 1 ◽  
Selective Blockade ◽  
Biologic Effects ◽  
Eta Receptor ◽  
Etb Receptor ◽  
Major Antigen ◽  
And Function

Abstract The biologic effects of endothelin-1 (ET-1) are not limited to its potent vasoconstricting activity. The endothelin receptors, ETA and ETB, have differential tissue and functional distributions. Here we showed that dendritic cells (DCs), the major antigen-presenting cells in the adaptive limb of the immune system, produce large amounts of ET-1 and significantly increase the expression of endothelin receptors upon maturation. Selective blockade of the ETA receptor significantly reduced expression of the mature DC marker CD83, decreased the production of the immunostimulatory cytokine interleukin-12, down-regulated DC ability to stimulate T cells, and promoted DC apoptosis. Selective ETB receptor blockade, on the other hand, resulted in increased expression of CD83 and improved DC survival. Therefore, ET-1/ETA/ETB autocrine/paracrine loops on DCs appear to be essential for the normal maturation and function of human DCs, presenting a unique target for immunomodulatory therapies. (Blood. 2004;104:2107-2115)

scholarly journals Novel mechanism of immunosuppression by influenza virus haemagglutinin: selective suppression of interleukin 12 p35 transcription in murine bone marrow-derived dendritic cells

2005 ◽  
Vol 86 (7) ◽  
pp. 1885-1890 ◽  
Author(s):  
Cariosa M. Noone ◽  
Ellen A. Lewis ◽  
Anne B. Frawely ◽  
Robert W. Newman ◽  
Bernard P. Mahon ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
Influenza Virus ◽  
Selective Inhibition ◽  
Interleukin 12 ◽  
Transcriptional Level ◽  
Virus Infections ◽  
Murine Bone Marrow ◽  
Major Antigen ◽  
Bacterial Superinfection

Infection with influenza virus strongly predisposes an individual to bacterial superinfection, which is often the significant cause of morbidity and mortality during influenza epidemics. Little is known about the immunomodulating properties of the virus that lead to this phenomenon, but the effect of the viral components on the development of immune dendritic cells (DCs) may prove vital. In this study, activation of and cytokine secretion by bacterial lipopolysaccharide (LPS)-stimulated bone marrow-derived dendritic cells (BMDCs) following treatment with the influenza virus major antigen haemagglutinin (HA) were examined. HA selectively inhibits the release of LPS-induced interleukin 12 (IL12) p70, which is independent of IL10 secretion. Suppression occurs at the transcriptional level, with selective inhibition of p35- and not p40-subunit mRNA expression. The downregulation of IL12 p70 by influenza HA is a novel and unexplored pathway that may be relevant in the predisposition to bacterial superinfection associated with influenza virus infections.

Analysis of vasocontractile responses to endothelin-1 in rabbit retinal vessels using an ETA receptor antagonist and an ETB receptor agonist

Life Sciences ◽  
1993 ◽  
Vol 53 (6) ◽  
pp. PL111-PL115 ◽  
Author(s):  
Kazuo Takei ◽  
Tsuyoshi Sato ◽  
Tomohito Nonoyama ◽  
Takashi Miyauchi ◽  
Katsutoshi Goto
Keyword(s):  
Receptor Antagonist ◽  
Receptor Agonist ◽  
Retinal Vessels ◽  
Endothelin 1 ◽  
Eta Receptor ◽  
Etb Receptor ◽  
Eta Receptor Antagonist

Inhibition of maturation and function of dendritic cells by intravenous immunoglobulin

Blood ◽  
2003 ◽  
Vol 101 (2) ◽  
pp. 758-765 ◽  
Author(s):  
Jagadeesh Bayry ◽  
Sébastien Lacroix-Desmazes ◽  
Cedric Carbonneil ◽  
Namita Misra ◽  
Vladimira Donkova ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Autoimmune Diseases ◽  
Intravenous Immunoglobulin ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Activity ◽  
Interleukin 12 ◽  
Immune Mediated ◽  
And Function

Normal immunoglobulin G for therapeutic use (intravenous immunoglobulin [IVIg]) is used in an increasing number of immune-mediated conditions, including acute and chronic/relapsing autoimmune diseases, transplantation, and systemic inflammatory disorders. Several mutually nonexclusive mechanisms of action account for the immunoregulatory effects of IVIg. Although IVIg inhibits T-cell proliferation and T-cell cytokine production, it is unclear whether these effects are directly dependent on the effects of IVIg on T cells or they are dependent through the inhibition of antigen-presenting cell activity. Here, we examined the effects of IVIg on differentiation, maturation, and function of dendritic cells (DCs). We show that IVIg inhibits the differentiation and maturation of DCs in vitro and abrogates the capacity of mature DC to secrete interleukin-12 (IL-12) on activation while enhancing IL-10 production. IVIg-induced down-regulation of costimulatory molecules associated with modulation of cytokine secretion resulted in the inhibition of autoreactive and alloreactive T-cell activation and proliferation. Modulation of DC maturation and function by IVIg is of potential relevance to its immunomodulatory effects in controlling specific immune responses in autoimmune diseases, transplantation, and other immune-mediated conditions.

Differential regulation of renal regional blood flow by endothelin-1

1996 ◽  
Vol 271 (6) ◽  
pp. F1166-F1172 ◽  
Author(s):  
K. Gurbanov ◽  
I. Rubinstein ◽  
A. Hoffman ◽  
Z. Abassi ◽  
O. S. Better ◽  
...  
Keyword(s):  
Blood Flow ◽  
Receptor Antagonist ◽  
Bolus Injection ◽  
Regional Blood Flow ◽  
Doppler Flowmetry ◽  
Endothelin 1 ◽  
Male Wistar Rats ◽  
Eta Receptor ◽  
Etb Receptor ◽  
Eta Receptor Antagonist

The present study evaluated the effects and mechanisms of action of endothelin-1 (ET-1) on medullary and cortical blood flow (MBF and CBF, respectively). CBF and MBF were measured simultaneously by laser-Doppler flowmetry in anesthetized male Wistar rats. Bolus injection of ET-1 (1.0 nmol/kg iv) produced a sustained decrease in CBF (delta = -30%) and a transient increase in MBF (delta = +35%). The medullary vasodilation induced by ET-1 was observed with doses lower than that required to produce cortical vasoconstriction; was completely blocked by bosentan, a mixed ETA/B-receptor antagonist; and was mimicked by IRL-1620, a specific ETB-receptor agonist. In contrast, BQ-123, an ETA-receptor antagonist, failed to inhibit the ET-1-dependent medullary vasodilation but effectively blocked the cortical vasoconstriction induced by the peptide. Finally, inhibition of nitric oxide (NO) synthase completely abolished, whereas cylooxygenase inhibition attenuated, the effect of ET-1 on MBF. The data demonstrate that ET-1 exerts opposite effects on renal cortical and medullary circulation, i.e., ETA-receptor-mediated cortical vasoconstriction and ETB-mediated medullary vasodilation. Furthermore, the medullary vasodilation induced by ET-1 is dependent on the NO system and, to a lesser extent, on prostaglandin generation.

scholarly journals Role of the Endothelin-1 System in the Luteolytic Process of Pseudopregnant Rabbits

Endocrinology ◽  
2005 ◽  
Vol 146 (3) ◽  
pp. 1293-1300 ◽  
Author(s):  
Cristiano Boiti ◽  
Gabriella Guelfi ◽  
Gabriele Brecchia ◽  
Cecilia Dall’Aglio ◽  
Piero Ceccarelli ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Prostaglandin F2α ◽  
Receptor Protein ◽  
Corpora Lutea ◽  
Positive Staining ◽  
Endothelin 1 ◽  
Cox Inhibitor ◽  
Eta Receptor ◽  
Etb Receptor

The aim of this study was to better understand the role of the endothelin-1 (ET-1) system in the process of controlling the corpora lutea (CL) life span in rabbits. ET-1 (10 μg iv) administration at d 9 and 12 of pseudopregnancy induced a functional luteolysis within 24 h of injection, but it was ineffective at both d 4 and 6. Pretreatments with Bosentan, a dual ETA/ETB receptor antagonist, or cyclooxygenase (COX) inhibitor blocked the luteolytic action of ET-1 but not that induced by prostaglandin F2α (PGF2α). In CL cultured in vitro, ET-1 increased (P ≤ 0.01) both PGF2α production and luteal nitric oxide synthase activity but decreased (P ≤ 0.01) progesterone release. Addition of ETA receptor antagonist BQ123 or COX inhibitor blocked the ET-1 luteolytic effects. Positive staining for ET-1 receptors was localized in ovarian blood vessels, granulosa cells of large follicles, and luteal cells. Immunoblot analysis of ET-1 receptor protein revealed a strong band of approximately 48 kDa in d-9 CL. Up to d 6 of pseudopregnancy, ET-1 mRNA abundance in CL was poorly expressed but then increased (P ≤ 0.01) at d 9 and 13. ETA-receptor transcript increased (P ≤ 0.01) at d 6, remained at the same level up to d 13, and then declined to the lowest (P ≤ 0.01) levels at d 22. ETB-receptor mRNA increased (P ≤ 0.01) throughout the late-luteal stage from d 13 up to d 18. Our data suggest that the luteolytic action of ET-1 may be a result of PGF2α synthesis from both luteal and accessory cells, via the COX pathways.

scholarly journals Autocrine effects of endothelin-1 on leukocyte-endothelial interaction: stimulation of endothelin B receptor subtype reduces endothelial adhesiveness via a nitric oxide-dependent mechanism

Blood ◽  
1996 ◽  
Vol 88 (10) ◽  
pp. 3894-3900 ◽  
Author(s):  
T Murohara ◽  
AM Lefer
Keyword(s):  
Nitric Oxide ◽  
Receptor Antagonist ◽  
Receptor Subtype ◽  
Endothelin 1 ◽  
Eta Receptor ◽  
Etb Receptor ◽  
Endothelin B ◽  
Eta Receptor Antagonist ◽  
Inhibition Of Thrombin

The effects of endothelin-1 (ET-1) on P-selectin-mediated leukocyte endothelial interaction were examined in vitro. Adherence of autologous polymorphonuclear leukocytes (PMNs) to the endothelium was markedly enhanced by endothelial stimulation with either (2 U/mL) thrombin, (1 mumol/L) histamine, or (100 nmol/L) phorbol myristate acetate (PMA). In contrast, ET-1 alone (10 and 100 nmol/L) only slightly increased the number of adhering PMNs. The increased PMN adherence to thrombin- or histamine-stimulated endothelium, which was blocked by an anti-P-selectin monoclonal antibody, was also significantly attenuated by preincubation of coronary segments with (100 nmol/L) ET-1. We further investigated the mechanism of this anti-adherence action of ET-1 on thrombin-stimulated endothelial adhesiveness. Preincubation of coronary segments with a selective ETA receptor antagonist, BQ485 (1 mumol/L), had no effect on ET-1 inhibition of thrombin-induced PMN adherence. In contrast, preincubation with a selective ETB receptor antagonist, BQ788 (1 mumol/L) significantly reversed ET-1 inhibition of thrombin-induced PMN adherence, whereas the selective ETB receptor agonist BQ-3020 mimicked the inhibitory action of ET-1 on thrombin-induced PMN adherence. Furthermore, (100 mumol/L) N omega-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, significantly attenuated ET-1 inhibition of thrombin-stimulated PMN adherence. These results suggest that ET-1 may inhibit P-selectin-mediated leukocyte-endothelial interaction via ETB receptor stimulation and subsequent endothelial NO formation. This autocrine effect of ET-1 may be involved in pathophysiologic states such as early atherogenesis by preventing leukocyte-endothelial interaction in constricted blood vessels.

Endothelin-1 induces mucosal mast cell degranulation and tissue injury via ETA receptors

2002 ◽  
Vol 103 (s2002) ◽  
pp. 31S-34S ◽  
Author(s):  
Mihály BOROS ◽  
László SZALAY ◽  
József KASZAKI
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Receptor Antagonist ◽  
Mast Cell Degranulation ◽  
Tissue Response ◽  
Mucosal Mast Cell ◽  
Receptor Antagonists ◽  
Endothelin 1 ◽  
Eta Receptor ◽  
Etb Receptor

The effects of endothelin-1 (ET-1) on mucosal mast cells are of special interest, since they may be an important component of the tissue response that occurs during ischaemic preconditioning or ischaemia/re-oxygenation injuries. Increasing doses of ET-1 were administered intravenously to anaesthetized rats. In a second series of experiments, animals were pretreated with the ETA receptor antagonists BQ-610 or ETR-P1/fl peptide, or with the ETB receptor antagonist IRL-1038. Intestinal perfusion changes were recorded, and the proportion of degranulated mast cells and the degree of mucosal damage were determined in ileal biopsies. ET-1 induced dose-dependent alterations in the haemodynamic and morphological parameters, and caused significant mast cell degranulation. These changes were inhibited significantly by pretreatment with the ETA receptor antagonists, but not with the ETB receptor antagonist. We conclude that a cross-talk exists between endothelial cell-derived humoral mediators and the intestinal mast cell system.

scholarly journals Regulation of IL-10 and IL-12 production and function in macrophages and dendritic cells

F1000Research ◽  
2015 ◽  
Vol 4 ◽  
pp. 1465 ◽  
Author(s):  
Xiaojing Ma ◽  
Wenjun Yan ◽  
Hua Zheng ◽  
Qinglin Du ◽  
Lixing Zhang ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Clinical Intervention ◽  
Interleukin 10 ◽  
Intervention Strategies ◽  
Interleukin 12 ◽  
Signaling Mechanisms ◽  
Wide Range ◽  
Human Disorders ◽  
And Function ◽  
Antigen Presenting

Interleukin-10 and Interleukin-12 are produced primarily by pathogen-activated antigen-presenting cells, particularly macrophages and dendritic cells. IL-10 and IL-12 play very important immunoregulatory roles in host defense and immune homeostasis. Being anti- and pro-inflammatory in nature, respectively, their functions are antagonistically opposing. A comprehensive and in-depth understanding of their immunological properties and signaling mechanisms will help develop better clinical intervention strategies in therapy for a wide range of human disorders. Here, we provide an update on some emerging concepts, controversies, unanswered questions, and opinions regarding the immune signaling of IL-10 and IL-12.

Interaction among ET-1, endothelium-derived nitric oxide, and prostacyclin in pulmonary arteries and veins

1994 ◽  
Vol 267 (1) ◽  
pp. H139-H147 ◽  
Author(s):  
T. M. Zellers ◽  
J. McCormick ◽  
Y. Wu
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Veins ◽  
Pulmonary Arteries ◽  
Endothelin 1 ◽  
Eta Receptor ◽  
Etb Receptor ◽  
Potent Vasoconstrictor ◽  
Eta Receptor Antagonist ◽  
Arteries And Veins

Endothelin-1 causes vasodilation of the intact porcine pulmonary vascular bed. To determine the cause of this vasodilation, we investigated the interactions of endothelin-1 (ET-1), endothelium-derived nitric oxide (EDNO), and prostacyclin in isolated small porcine pulmonary arteries and veins under in vitro conditions. ET-1 caused concentration-dependent contractions in arteries and veins, augmented by the nitric oxide synthase (NOS) inhibitor, N omega-nitro-L-arginine, in pulmonary veins. BQ-123 (ETA-receptor antagonist) depressed the ET-1-induced contractions. Sarafotoxin S6C, an ETB-receptor agonist, caused contractions of pulmonary veins only. Endothelium-dependent relaxations to bradykinin and ET-1 were greater in pulmonary veins compared with arteries, inhibited by N omega-nitro-L-arginine, and reversed by L-arginine. BQ-123 augmented ET-1-induced arterial relaxation. ET-3 and sarafotoxin S6C, ETB-receptor agonists, caused comparable endothelium-dependent relaxations in arteries and veins. ET-1 caused a fourfold greater increase in prostacyclin release in pulmonary veins compared with arteries. We conclude that ET-1 is a potent vasoconstrictor of porcine pulmonary vessels and stimulates the release of EDNO and prostacyclin, which oppose the contractions to the peptide. The release of these endothelium-derived vasodilators appears greater in pulmonary veins.

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