DP1 receptor signaling prevents the onset of intrinsic apoptosis in eosinophils and functions as a transcriptional modulator

Prostaglandin (PG) D2 is the ligand for the G‐protein coupled receptors DP1 (D‐type prostanoid receptor 1) and DP2 (also known as chemoattractant receptor homologous molecule, expressed on Th2 cells; CRTH2). Both, DP1 and DP2 are expressed on the cellular surface of eosinophils; although it has become quite clear that PGD2 induces eosinophil migration mainly via DP2 receptors, the role of DP1 in eosinophil responses has remained elusive. In this study, we addressed how DP1 receptor signaling complements the pro‐inflammatory effects of DP2. We found that PGD2 prolongs the survival of eosinophils via a DP1 receptor‐mediated mechanism that inhibits the onset of the intrinsic apoptotic cascade. The DP1 agonist BW245c prevented the activation of effector caspases in eosinophils and protected mitochondrial membranes from depolarization which—as a consequence—sustained viability of eosinophils. DP1 activation in eosinophils enhanced the expression of the anti‐apoptotic gene BCL‐XL, but also induced pro‐inflammatory genes, such as VLA‐4 and CCR3. In HEK293 cells that overexpress recombinant DP1 and/or DP2 receptors, activation of DP1, but not DP2, delayed cell death and stimulated proliferation, along with induction of serum response element (SRE), a regulator of anti‐apoptotic, early‐response genes. We conclude that DP1 receptors promote the survival via SRE induction and induction of pro‐inflammatory genes. Therefore, targeting DP1 receptors, along with DP2, may contribute to anti‐inflammatory therapy in eosinophilic diseases

Prostaglandins and Their Receptors in Eosinophil Function and As Therapeutic Targets

Of the known prostanoid receptors, human eosinophils express the prostaglandin D2 (PGD2) receptors DP1 [also D-type prostanoid (DP)] and DP2 (also chemoattractant receptor homologous molecule, expressed on Th2 cells), the prostaglandin E2 receptors EP2 and EP4, and the prostacyclin (PGI2) receptor IP. Prostanoids can bind to either one or multiple receptors, characteristically have a short half-life in vivo, and are quickly degraded into metabolites with altered affinity and specificity for a given receptor subtype. Prostanoid receptors signal mainly through G proteins and naturally activate signal transduction pathways according to the G protein subtype that they preferentially interact with. This can lead to the activation of sometimes opposing signaling pathways. In addition, prostanoid signaling is often cell-type specific and also the combination of expressed receptors can influence the outcome of the prostanoid impulse. Accordingly, it is assumed that eosinophils and their (patho-)physiological functions are governed by a sensitive prostanoid signaling network. In this review, we specifically focus on the functions of PGD2, PGE2, and PGI2 and their receptors on eosinophils. We discuss their significance in allergic and non-allergic diseases and summarize potential targets for drug intervention

Cytokines and their association with insulin resistance in obese pregnant women with different levels of physical activity

Background: Cytokines contribute to insulin resistance in pregnancy, but the role of distinct cytokines is not fully understood. Objectives: To study whether cytokines produced by tissues other than skeletal muscle are associated with glucose and insulin metabolism activity in overweight and obese women and to study whether these associations can be modified by physical activity. Methods: A longitudinal study with 44 overweight and obese pregnant women was conducted. Changes in cytokines levels (IFN-gamma, IP-10, IL1-alpha MIP1-alpha, adiponectin and leptin) and ICAM1 from early (15 wk) to late (32 wk) pregnancy were determined. Physical activity was measured objectively with accelerometers. In linear regression models, the associations between (changes in) cytokine levels and fasting glucose, fasting insulin and HOMA-IR were studied. Results: Both IFN-gamma and IP-10 levels increased from early to late pregnancy, and adiponectin levels decreased. IFN-gamma and IP-10 were positively associated with fasting glucose, whereas IL-1 alpha , ICAM1 and adiponectin were inversely associated with insulin and insulin resistance. The association of IL-l alpha with insulin and insulin resistance was only found in women with low levels of physical activity. Conclusions: IFN-gamma, IP-10, IL1-alpha, ICAM1, and adiponectin may play a role in glucose and insulin metabolism in pregnancy. The relationship of IL-1 alpha with insulin and insulin resistance might be moderated by levels of physical activity. Further studies are required to confirm the role of these cytokines in glucose and insulin metabolism in obese pregnant women. (C) 2015 Elsevier Ltd. All rights reserved

Supplementary Material for: Gesundheitsförderung durch Stress- und Burnout-Prophylaxe mit ätherischen Ölen für alle Berufsgruppen im Wiener Otto-Wagner-Spital

<b><i>Hintergrund: </i></b>Mehr als 50% der Menschen leiden an berufsbedingtem und familiärem Stress, der bei hohem Pegel zu körperlichen, mentalen und sozialen Beeinträchtigungen bis hin zum Burnout-Syndrom führen kann. Die regelmäßige Anwendung von hochwertigen ätherischen Ölen vermag den individuellen Stresspegel deutlich zu senken. In einem Projekt zur Gesundheitsförderung durch Stress- und Burnout-Prophylaxe soll die Stressreduktion durch ätherische Öle bestätigt werden. <b><i>Methodik:</i></b> In das Studienprojekt konnten insgesamt 88 Mitarbeiter des Wiener Otto Wagner Spitals mit auswertbaren Aufnahme- und 55 Mitarbeiter mit auswertbaren Abschluss-Fragebögen aufgenommen werden. Die Teilnehmer erhielten einen SOS-Stress-Deoroller mit 12 ätherischen Ölen, der mindestens 3-mal täglich einen Monat lang an den Pulszonen der Handgelenke aufgetragen wurde. <b><i>Ergebnisse: </i></b>Zum Befragungszeitpunkt 1 am Tag der Aufnahme in die Studie betrug der Stresswert bezogen auf eine Stress-Skala von 1 (gar nicht belastet) bis 10 (sehr stark belastet) im Mittel 6,28, am Ende der Beobachtungszeit 5,24. In der Analyse der körperlichen Beeinträchtigungen durch Stress (SK 1-8) zeigte sich beim Pflegepersonal (p = 0,036) und bei Personen über 50 Jahren (p = 0,012 bzw. 0,025) ein signifikanter Benefit der Aromatherapie. Das Belastungsniveau durch körperlichen, psychischen und sozialen Stress zwischen Befragungszeitpunkt 1 und 2 zeigte deutliche, mitunter signifikante positive Veränderung durch die Anwendung der ätherischen Öle. Bei 27 Teilnehmern konnten die Fragebögen von Zeitpunkt 1 und 2 dem jeweiligen Teilnehmer zugeordnet werden. In dieser Personengruppe zeigten sich sowohl in der Gesamtbelastung wie auch in allen Teilbereichen signifikant positive Ergebnisse der Aromatherapie. <b><i>Schlussfolgerung: </i></b>Ein Großteil der Teilnehmer konnte mittels der ätherischen Öle im SOS-Stress-Deoroller seine Stress-assoziierten Beeinträchtigungen deutlich reduzieren. Es konnten keine allergischen Reaktionen oder Unverträglichkeiten beobachtet werden. Ausgewählte hochwertige ätherische Öle können für die Prophylaxe und Behandlung von Stress und Burnout empfohlen werden

Sedentary behavior in obese pregnant women is associated with inflammatory markers and lipid profile but not with glucose metabolism

AbstractBackgroundSedentary behavior is an independent risk factor for the metabolic syndrome, but the role of sedentary behavior in the development of gestational diabetes is unclear.ObjectivesThis study tested the hypothesis that less sedentary behavior is related to better insulin sensitivity, lipid and cytokine profile in obese pregnant women.MethodsA longitudinal observational study with 46 overweight and obese pregnant women was conducted. Sedentary behavior was measured objectively using accelerometers at 15, 24 and 32weeks of gestation, and at those time points fasting blood was taken as well. A 100g oral glucose tolerance test was performed at 24 and 32weeks. Levels of glucose, insulin, total cholesterol, HDL, LDL, triglycerides were measured, as well as cytokines. The relationship between sedentary behavior and metabolic outcomes was assessed using linear regression analysis.ResultsWomen spent almost 60% of their time sitting throughout pregnancy. In cross-sectional analyses, an association of sedentary time at 24weeks was found with increased total cholesterol and HDL. More sedentary time was associated with lower IL-6 at 24weeks and with higher IL-10, TNF-α and leptin levels at 32weeks of pregnancy. Changes in sedentary time were not associated with changes in any of the metabolic outcomes.ConclusionsIn conclusion, time spent sedentary in pregnancy was associated with lipid and cytokine profile. Whether decreasing sedentary time beneficially influences lipid profile and influences cytokine profiles of overweight and obese women needs to be assessed in future intervention studies

The prostaglandin D2 receptor 2 pathway in asthma: a key player in airway inflammation

Abstract Asthma is characterised by chronic airway inflammation, airway obstruction and hyper-responsiveness. The inflammatory cascade in asthma comprises a complex interplay of genetic factors, the airway epithelium, and dysregulation of the immune response. Prostaglandin D2 (PGD2) is a lipid mediator, predominantly released from mast cells, but also by other immune cells such as TH2 cells and dendritic cells, which plays a significant role in the pathophysiology of asthma. PGD2 mainly exerts its biological functions via two G-protein-coupled receptors, the PGD2 receptor 1 (DP1) and 2 (DP2). The DP2 receptor is mainly expressed by the key cells involved in type 2 immune responses, including TH2 cells, type 2 innate lymphoid cells and eosinophils. The DP2 receptor pathway is a novel and important therapeutic target for asthma, because increased PGD2 production induces significant inflammatory cell chemotaxis and degranulation via its interaction with the DP2 receptor. This interaction has serious consequences in the pulmonary milieu, including the release of pro-inflammatory cytokines and harmful cationic proteases, leading to tissue remodelling, mucus production, structural damage, and compromised lung function. This review will discuss the importance of the DP2 receptor pathway and the current understanding of its role in asthma