Cyclooxygenase inhibition in human monocytes increases endotoxin-induced TNFα without affecting cyclooxygenase-2 expression

Ulcar, R; Peskar, Bernhard A.; Schuligoi, Rufina; Heinemann, Ákos; Kessler, Harald H.; Santner, Brigitte I.; Amann, Rainer

doi:10.1016/j.ejphar.2004.08.003

Cited by 14 publications

(11 citation statements)

References 25 publications

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“…Moreover, adhesion of platelets to fibrinogen under flow conditions and in vitro thrombus formation were similarly prevented by the EP4 agonist [41]. Other anti-inflammatory actions of EP4 receptors reported previously include inhibition of cytokine production in monocytes and macrophages [42][43][44], and mucus secretion in airway epithelial cells [45]. From our current data, we cannot exclude the possibility that parts of the inhibitory effects of PGE 2 and the EP4 agonist also involve EP4 receptors expressed on the endothelial cells.…”

Section: Discussioncontrasting

confidence: 41%

Interaction of eosinophils with endothelial cells is modulated by prostaglandin EP4 receptors

et al. 2011

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Eosinophil extravasation across the endothelium is a key feature of allergic inflammation. Here, we investigated the role of PGE 2 and its receptor, E-type prostanoid receptor (EP)-4, in the regulation of eosinophil interaction with human pulmonary microvascular endothelial cells. PGE 2 and the EP4 receptor agonist ONO AE1-329 significantly reduced eotaxininduced eosinophil adhesion to fibronectin, and formation of filamentous actin and gelsolin-rich adhesive structures. These inhibitory effects were reversed by a selective EP4 receptor antagonist, ONO AE3-208. PGE 2 and the EP4 agonist prevented the activation and cell-surface clustering of b2 integrins, and L-selectin shedding of eosinophils. Under physiological flow conditions, eosinophils that were treated with the EP4 agonist showed reduced adhesion to endothelial monolayers upon stimulation with eotaxin, as well as after TNF-a-induced activation of the endothelial cells. Selective activation of EP1, EP2, and EP3 receptors did not alter eosinophil adhesion to endothelial cells, whereas the EP4 antagonist prevented PGE 2 from decreasing eosinophil adhesion. Finally, eosinophil transmigration across thrombin-and TNF-a-activated endothelial cells was effectively reduced by the EP4 agonist. These data suggest that PGE 2 -EP4 signaling might be protective against allergic responses by inhibiting the interaction of eosinophils with the endothelium and might hence be a useful therapeutic option for controlling inappropriate eosinophil infiltration.Keywords: Adhesion . Endothelium . Eosinophils . Migration . Prostaglandins Supporting Information available online IntroductionEosinophil granulocytes are important effector cells in allergic inflammation and are recruited to the tissue by chemotactic signals [1][2][3][4][5]. The infiltrating eosinophils release several toxic and proinflammatory mediators which induce epithelial injury, airway hyper-responsiveness, and airway remodeling [6][7][8]. Therefore, eosinophils are regarded as potential therapeutic targets in allergic diseases and asthma [9].Prostaglandins (PGs) play diverse roles in inflammation, depending on the cellular context, the type of PG being released, and the differential expression of PG receptors [10,11]. While PGD 2, which is the predominant PG formed in mast cells, exerts proinflammatory effects by regulating the recruitment of eosino- Eur. J. Immunol. 2011. 41: 2379-2389 DOI 10.1002 Leukocyte signaling 2379 phils, basophils, and Th2 lymphocytes to the sites of allergic inflammation [12], PGE 2 seems to attenuate inflammatory responses and reduce tissue injury in airways [13]. PGE 2 was found to exert bronchoprotective effects in patients with asthma [14]. In rats, the ovalbumin-induced early and late phase airway responses were inhibited by intratracheally administered PGE 2 [15]. The activity of PGE 2 is mediated by four subtypes of E-type prostanoid receptors (EP), EP1, EP2, EP3, and EP4 [16]. These G protein-coupled receptors have distinct biological imprints depending on their affinity with...

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Section: Discussioncontrasting

confidence: 41%

Interaction of eosinophils with endothelial cells is modulated by prostaglandin EP4 receptors

et al. 2011

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“…Aliquots were placed into 6.5-mm Transwell inserts with 5-m polycarbonate filters (Corning) in 24-well culture plates and human AB serum was added. After 120 min of incubation at 37°C (5% CO 2 ) nonadherent cells were removed, which resulted in 10 5 monocytes per well and a purity of 95% (32).…”

Section: Culture Of Human Peripheral Blood Monocytesmentioning

confidence: 99%

Prostaglandin E2 Inhibits Eosinophil Trafficking through E-Prostanoid 2 Receptors

Sturm

Schratl

Schuligoi

et al. 2008

The Journal of Immunology

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108

110

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The accumulation of eosinophils in lung tissue is a hallmark of asthma, and it is believed that eosinophils play a crucial pathogenic role in allergic inflammation. Prostaglandin (PG) E2 exerts anti-inflammatory and bronchoprotective mechanisms in asthma, but the underlying mechanisms have remained unclear. In this study we show that PGE2 potently inhibits the chemotaxis of purified human eosinophils toward eotaxin, PGD2, and C5a. Activated monocytes similarly attenuated eosinophil migration, and this was reversed after pretreatment of the monocytes with a cyclooxygenase inhibitor. The selective E-prostanoid (EP) 2 receptor agonist butaprost mimicked the inhibitory effect of PGE2 on eosinophil migration, whereas an EP2 antagonist completely prevented this effect. Butaprost, and also PGE2, inhibited the C5a-induced degranulation of eosinophils. Moreover, selective kinase inhibitors revealed that the inhibitory effect of PGE2 on eosinophil migration depended upon activation of PI3K and protein kinase C, but not cAMP. In animal models, the EP2 agonist butaprost inhibited the rapid mobilization of eosinophils from bone marrow of the in situ perfused guinea pig hind limb and prevented the allergen-induced bronchial accumulation of eosinophils in OVA-sensitized mice. Immunostaining showed that human eosinophils express EP2 receptors and that EP2 receptor expression in the murine lungs is prominent in airway epithelium and, after allergen challenge, in peribronchial infiltrating leukocytes. In summary, these data show that EP2 receptor agonists potently inhibit eosinophil trafficking and activation and might hence be a useful therapeutic option in eosinophilic diseases.

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“…Aliquots of 500 µl were placed into 24-well culture plates and human AB serum was added. Nonadherent cells were removed after 2 h of incubation at 37°C (5% CO 2 ), which results in about 5 × 10 4 monocytes per well at a purity of >95% [14]. Cells were then stimulated with LPS (10 ng/ml) in the absence or presence of exogenously added PGE 2 for 4 h or after pretreatment with acetylsalicylic acid (as water-soluble lysine-acetylsalicylic acid, 300 µmol/l).…”

Section: Methodsmentioning

confidence: 99%

“…Peripheral blood mononuclear cells (containing monocytes and lymphocytes) were prepared by dextran sedimentation followed by centrifugation of leukocytes over Histopaque gradients as described [14]. Peripheral blood mononuclear cells were resuspended in RPMI-1640 supplemented with penicillin (100 U/ml), streptomycin (100 µg/ml), glutamine (20 mmol/l), nonessential amino acids, HEPES (50 mmol/l), and sodium pyruvate (10 mmol/l) at 1 × 10 6 /ml.…”

Section: Methodsmentioning

confidence: 99%

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Altered Inhibitory Function of the E-Type Prostanoid Receptor 4 in Eosinophils and Monocytes from Aspirin-Intolerant Patients

Luschnig¹,

Frei²,

Lang‐Loidolt

et al. 2014

Pharmacology

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Prostaglandin (PG) E₂ has been implicated in the pathogenesis of aspirin-exacerbated respiratory disease (AERD). E-type prostanoid (EP) receptor 4 is known to confer inhibitory signals to eosinophils and monocytes, amongst others. In this study, we investigated whether the responsiveness of eosinophils and monocytes to PGE₂ and EP4 receptor activation is altered in AERD patients. While the expression of the EP4 receptor in eosinophils was unaltered in AERD patients, inhibition of eosinophil chemotaxis by PGE₂ or the EP4 agonist CAY10598 was less pronounced in AERD patients as compared to healthy control subjects. In monocytes, we found no changes in basal or lipopolysaccharide (LPS)-stimulated PGE₂ synthesis, but the response to EP4 receptor activation with respect to inhibition of LPS-induced tumor necrosis factor-α release was reduced in AERD patients, especially in the presence of aspirin (acetylsalicylic acid). Our data point towards a decreased sensitivity of inhibitory EP4 receptor that may play a role in AERD.

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Cyclooxygenase inhibition in human monocytes increases endotoxin-induced TNFα without affecting cyclooxygenase-2 expression

Cited by 14 publications

References 25 publications

Interaction of eosinophils with endothelial cells is modulated by prostaglandin EP4 receptors

Interaction of eosinophils with endothelial cells is modulated by prostaglandin EP4 receptors

Prostaglandin E2 Inhibits Eosinophil Trafficking through E-Prostanoid 2 Receptors

Altered Inhibitory Function of the E-Type Prostanoid Receptor 4 in Eosinophils and Monocytes from Aspirin-Intolerant Patients

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