15-Deoxy-Δ12,1412,14-prostaglandins D2 and J2 Are Potent Activators of Human Eosinophils

Monneret, Guillaume; Li, Hongping; Vasilescu, Julian; Rokach, Joshua; Powell, William S.

doi:10.4049/jimmunol.168.7.3563

Cited by 110 publications

(111 citation statements)

References 50 publications

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“…The potency of ⌬ 12 -PGJ 2 was similar to those of PGJ 2 and 15-deoxy-⌬ 12,14 -PGJ 2 , but 30 times lower than that of eotaxin or PGD 2 . Similar concentration-response relationships had previously been reported for eosinophil actin polymerization induced by these PGD 2 analogs (15). From these data it appeared likely that PGJ 2 and ⌬ 12 -PGJ 2 might also act as chemoattractants, and our data show that these PGD 2 metabolites did induce concentration-dependent chemotaxis of purified eosinophils with the same efficacy as the other eosinophil-stimulating agonists, eotaxin and PGD 2 .…”

Section: Discussionsupporting

confidence: 74%

“…PGJ 2 and ⌬ 12 -PGJ 2 have also been shown to induce actin polymerization and CD11b up-regulation (15), and in the current study we show that PGJ 2 and ⌬ 12 -PGJ 2 are, in fact, potent eosinophil chemoattractants and inducers of respiratory burst. The rapid conversion of PGD 2 to ⌬ 12 -PGJ 2 in plasma (10), however, suggests that it is ⌬ 12 -PGJ 2 rather than PGD 2 that might have an impact on the intravascular pool of eosinophils.…”

Section: E Osinophils Are Important Effector Cells In Allergic Diseasesmentioning

confidence: 53%

“…Several PGD 2 metabolites, such as dihydro-15-keto-PGD 2 , 15-deoxy-⌬ 12,14 -PGJ 2 , and 15-deoxy-⌬ 12,14 -PGD 2 , have recently been characterized as potent eosinophil activators with respect to chemotaxis, actin polymerization, L-selectin shedding, and CD11b up-regulation (6,7,15). PGJ 2 and ⌬ 12 -PGJ 2 have also been shown to induce actin polymerization and CD11b up-regulation (15), and in the current study we show that PGJ 2 and ⌬ 12 -PGJ 2 are, in fact, potent eosinophil chemoattractants and inducers of respiratory burst.…”

Section: E Osinophils Are Important Effector Cells In Allergic Diseasesmentioning

confidence: 99%

“…Intracellular calcium levels were analyzed by flow cytometry as previously described (15). Polymorphonuclear leukocytes (10 7 cells/ml) were treated with 2 M of the acetoxymethyl ester of Fluo-3 in the presence of 0.02% Pluronic F-127 for 60 min at room temperature and were washed in PBS without Ca 2ϩ /Mg 2ϩ .…”

Section: Calcium Fluxmentioning

confidence: 99%

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Δ12-Prostaglandin J2, a Plasma Metabolite of Prostaglandin D2, Causes Eosinophil Mobilization from the Bone Marrow and Primes Eosinophils for Chemotaxis

Heinemann

Schuligoi

Sabroe

et al. 2003

The Journal of Immunology

101

138

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PGD2, a major mast cell mediator, is a potent eosinophil chemoattractant and is thought to be involved in eosinophil recruitment to sites of allergic inflammation. In plasma, PGD2 is rapidly transformed into its major metabolite Δ12-PGJ2, the effect of which on eosinophil migration has not yet been characterized. In this study we found that Δ12-PGJ2 was a highly effective chemoattractant and inducer of respiratory burst in human eosinophils, with the same efficacy as PGD2, PGJ2, or 15-deoxy-Δ12,14-PGJ2. Moreover, pretreatment of eosinophils with Δ12-PGJ2 markedly enhanced the chemotactic response to eotaxin, and in this respect Δ12-PGJ2 was more effective than PGD2. Δ12-PGJ2-induced facilitation of eosinophil migration toward eotaxin was not altered by specific inhibitors of intracellular signaling pathways relevant to the chemotactic response, phosphatidylinositol 3-kinase (LY-294002), mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (U-0126), or p38 mitogen-activated protein kinase (SB-202190). Desensitization studies using calcium flux suggested that Δ12-PGJ2 signaled through the same receptor, CRTH2, as PGD2. Finally, Δ12-PGJ2 was able to mobilize mature eosinophils from the bone marrow of the guinea pig isolated perfused hind limb. Given that Δ12-PGJ2 is present in the systemic circulation at relevant levels, a role for this PGD2 metabolite in eosinophil release from the bone marrow and in driving eosinophil recruitment to sites of inflammation appears conceivable.

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Section: Discussionsupporting

confidence: 74%

Section: E Osinophils Are Important Effector Cells In Allergic Diseasesmentioning

confidence: 53%

Section: E Osinophils Are Important Effector Cells In Allergic Diseasesmentioning

confidence: 99%

Section: Calcium Fluxmentioning

confidence: 99%

See 2 more Smart Citations

Δ12-Prostaglandin J2, a Plasma Metabolite of Prostaglandin D2, Causes Eosinophil Mobilization from the Bone Marrow and Primes Eosinophils for Chemotaxis

Heinemann

Schuligoi

Sabroe

et al. 2003

The Journal of Immunology

101

138

View full text Add to dashboard Cite

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“…In addition, CRTH2 is activated by several PGD 2 metabolites, including 13,14-dihydro-15-keto-(DK)-PGD 2 , PGJ 2 , ⌬ 12 PGJ 2 , and 15-deoxy-PGJ 2 (7,8) and a thromboxane (TX) metabolite, 11-dehydro-TXB 2 (9). Moreover, CRTH2 mediates the respiratory burst and degranulation of eosinophils (8,10), induces the production of proinflammatory cytokines in Th2 cells (11), and enhances the release of histamine from basophils (12).…”

Section: P Rostaglandin (Pg)mentioning

confidence: 99%

The Role of the Prostaglandin D2 Receptor, DP, in Eosinophil Trafficking

Schratl¹,

Royer²,

Kostenis³

et al. 2007

The Journal of Immunology

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Prostaglandin (PG) D2 is a major mast cell product that acts via two receptors, the D-type prostanoid (DP) and the chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) receptors. Whereas CRTH2 mediates the chemotaxis of eosinophils, basophils, and Th2 lymphocytes, the role of DP has remained unclear. We report in this study that, in addition to CRTH2, the DP receptor plays an important role in eosinophil trafficking. First, we investigated the release of eosinophils from bone marrow using the in situ perfused guinea pig hind limb preparation. PGD2 induced the rapid release of eosinophils from bone marrow and this effect was inhibited by either the DP receptor antagonist BWA868c or the CRTH2 receptor antagonist ramatroban. In contrast, BWA868c did not inhibit the release of bone marrow eosinophils when this was induced by the CRTH2-selective agonist 13,14-dihydro-15-keto-PGD2. In additional experiments, we isolated bone marrow eosinophils from the femoral cavity and found that these cells migrated toward PGD2. We also observed that BWA868c inhibited this response to a similar extent as ramatroban. Finally, using immunohistochemistry we could demonstrate that eosinophils in human bone marrow specimens expressed DP and CRTH2 receptors at similar levels. Eosinophils isolated from human peripheral blood likewise expressed DP receptor protein but at lower levels than CRTH2. In agreement with this, the chemotaxis of human peripheral blood eosinophils was inhibited both by BWA868c and ramatroban. These findings suggest that DP receptors comediate with CRTH2 the mobilization of eosinophils from bone marrow and their chemotaxis, which might provide the rationale for DP antagonists in the treatment of allergic disease.

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PACAP27 mitigates an age‐dependent hippocampal vulnerability to PGJ2‐induced spatial learning deficits and neuroinflammation in mice

et al. 2019

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BackgroundInflammation in the brain is mediated by the cyclooxygenase pathway, which leads to the production of prostaglandins. Prostaglandin (PG) D2, the most abundant PG in the brain, increases under pathological conditions and is spontaneously metabolized to PGJ2. PGJ2 is highly neurotoxic, with the potential to transition neuroinflammation into a chronic state and contribute to neurodegeneration as seen in many neurological diseases. Conversely, PACAP27 is a lipophilic peptide that raises intracellular cAMP and is an anti‐inflammatory agent. The aim of our study was to investigate the therapeutic potential of PACAP27 to counter the behavioral and neurotoxic effects of PGJ2 observed in aged subjects.MethodsPGJ2 was injected bilaterally into the hippocampal CA1 region of 53‐week‐old and 12‐week‐old C57BL/6N male mice, once per week over 3 weeks (three total infusions) and included co‐infusions of PACAP27 within respective treatment groups. Our behavioral assessments looked at spatial learning and memory performance on the 8‐arm radial maze, followed by histological analyses of fixed hippocampal tissue using Fluoro‐Jade C and fluorescent immunohistochemistry focused on IBA‐1 microglia.ResultsAged mice treated with PGJ2 exhibited spatial learning and long‐term memory deficits, as well as neurodegeneration in CA3 pyramidal neurons. Aged mice that received co‐infusions of PACAP27 exhibited remediated learning and memory performance and decreased neurodegeneration in CA3 pyramidal neurons. Moreover, microglial activation in the CA3 region was also reduced in aged mice cotreated with PACAP27.ConclusionsOur data show that PGJ2 can produce a retrograde spread of damage not observed in PGJ2‐treated young mice, leading to age‐dependent neurodegeneration of hippocampal neurons producing learning and memory deficits. PACAP27 can remediate the behavioral and neurodegenerative effects that PGJ2 produces in aged subjects. Targeting specific neurotoxic prostaglandins, such as PGJ2, offers great promise as a new therapeutic strategy downstream of cyclooxygenases, to combat the neuronal deficits induced by chronic inflammation.

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15-Deoxy-Δ12,1412,14-prostaglandins D2 and J2 Are Potent Activators of Human Eosinophils

Cited by 110 publications

References 50 publications

Δ12-Prostaglandin J2, a Plasma Metabolite of Prostaglandin D2, Causes Eosinophil Mobilization from the Bone Marrow and Primes Eosinophils for Chemotaxis

Δ12-Prostaglandin J2, a Plasma Metabolite of Prostaglandin D2, Causes Eosinophil Mobilization from the Bone Marrow and Primes Eosinophils for Chemotaxis

The Role of the Prostaglandin D2 Receptor, DP, in Eosinophil Trafficking

PACAP27 mitigates an age‐dependent hippocampal vulnerability to PGJ2‐induced spatial learning deficits and neuroinflammation in mice

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