Prostaglandin-E2 enhances EPO-mediated STAT5 transcriptional activity by serine phosphorylation of CREB

Boer, Arjen‐Kars; Drayer, A. Lyndsay; Rui, Hallgeir; Vellenga, Edo

doi:10.1182/blood.v100.2.467

Cited by 51 publications

(37 citation statements)

References 43 publications

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“…In contrast to our results, expression level of SOCS3 mRNA induced by PGE 2 is lower than those induced by IL-10. Also another report demonstrated that PGE 2 increases erythropoietin-dependent STAT5 regulatory genes, such as SOCS3 (31). This costimulatory effect of PGE 2 on erythropoietin-mediated STAT5 transactivation is mediated by the cAMP/PKA/CREB pathway, without affecting the STAT5 tyrosine phosphorylation or STAT5 DNA binding.…”

Section: Discussionmentioning

confidence: 89%

Prostaglandin E2 Augments IL-10 Signaling and Function

Cheon

Rho

Choi

et al. 2006

The Journal of Immunology

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In inflamed joints of rheumatoid arthritis, PGE2 is highly expressed, and IL-10 and IL-6 are also abundant. PGE2 is a well-known activator of the cAMP signaling pathway, and there is functional cross-talk between cAMP signaling and the Jak-STAT signaling pathway. In this study, we evaluated the modulating effect of PGE2 on STAT signaling and its biological function induced by IL-10 and IL-6, and elucidated its mechanism in THP-1 cells. STAT phosphorylation was determined by Western blot, and gene expression was analyzed using real-time PCR. Pretreatment with PGE2 significantly augmented IL-10-induced STAT3 and STAT1 phosphorylation, as well as suppressors of cytokine signaling 3 (SOCS3) and IL-1R antagonist gene expression. In contrast, PGE2 suppressed IL-6-induced phosphorylation of STAT3 and STAT1. These PGE2-induced modulating effects were largely reversed by actinomycin D. Pretreatment with dibutyryl cAMP augmented IL-10-induced, but did not change IL-6-induced STAT3 phosphorylation. Misoprostol, an EP2/3/4 agonist, and butaprost, an EP2 agonist, augmented IL-10-induced STAT3 phosphorylation and SOCS3 gene expression, but sulprostone, an EP1/3 agonist, had no effect. H89, a protein kinase A inhibitor, and LY294002, a PI3K inhibitor, diminished PGE2-mediated augmentation of IL-10-induced STAT3 phosphorylation. In this study, we found that PGE2 selectively regulates cytokine signaling via increased intracellular cAMP levels and de novo gene expression, and these modulating effects may be mediated through EP2 or EP4 receptors. PGE2 may modulate immune responses by alteration of cytokine signaling in THP-1 cells.

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Section: Discussionmentioning

confidence: 89%

Prostaglandin E2 Augments IL-10 Signaling and Function

Cheon

Rho

Choi

et al. 2006

The Journal of Immunology

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“…In the presence of Epo, Signal transducer and activator of transcription 5 (STAT5) is recruited to the Epo receptor and phosphorylated by the Janus kinase 2 (JAK2). Once phosphorylated, STAT5 is released from EpoR, homodimerizes in the cytosol, and translocates to the nucleus where it activates its target gene expression, including Bcl-X and cyclin D1 (53)(54)(55)(56)(57)(58). Phosphorylation of CREB by PKA enhances Epo-stimulated STAT5 transactivation by inducing recruitment of CREB/CBP/p300 to the STAT5 transactivational complex (58,59).…”

Section: Discussionmentioning

confidence: 99%

Inactivation of G-protein-coupled Receptor 48 (Gpr48/Lgr4) Impairs Definitive Erythropoiesis at Midgestation through Down-regulation of the ATF4 Signaling Pathway

Song

Luo

et al. 2008

Journal of Biological Chemistry

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G-protein-coupled receptors (GPCRs), one of the most versatile groups of cell surface receptors, can recognize specific ligands from neural, hormonal, and paracrine organs and regulate cell growth, proliferation, and differentiation. Gpr48/LGR4 is a recently identified orphan GPCR with unknown functions. To reveal the functions of Gpr48 in vivo, we generated Gpr48 ؊/؊ mice and found that Gpr48 ؊/؊ fetuses displayed transient anemia during midgestation and abnormal definitive erythropoiesis. The dramatic decrease of definitive erythroid precursors (Ter119 pos population) in Gpr48 ؊/؊ fetal liver at E13.5 was confirmed by histological analysis and blood smear assays. Real-time PCR analyses showed that in Gpr48؊/؊ mice both adult hemoglobin ␣ and ␤ chains were decreased while embryonic hemoglobin chains (, ␤H1, and ⑀y) were increased, providing another evidence for the impairment of definitive erythropoiesis. Furthermore, proliferation was suppressed in Gpr48 ؊/؊ fetal liver with decreased c-Myc and cyclin D1 expression, whereas apoptosis was unaffected. ATF4, a key transcription factor in erythropoiesis, was downregulated in Gpr48 ؊/؊ fetal livers during midgestation stage through the cAMP-PKA-CREB pathway, suggesting that Gpr48 regulated definitive erythropoiesis through ATF4-mediated definitive erythropoiesis.Erythropoiesis occurs sequentially in distinct anatomical locations in two different phases during embryogenesis. The earlier phase is defined as primitive erythropoiesis, which, in the mouse, originates from the yolk sac at embryonic day 7.5 (E7.5), 3 and the later phase is definitive erythropoiesis, which was carried out in the fetal liver during midgestation after E12.5. Non-nucleated adult-type red blood cells are first generated in the fetal liver, the primary organ for erythropoiesis during midgestation from E12 to E16 (1). Erythropoiesis then transfers to bone marrow and spleen in the adult (2, 3). However, the molecular mechanism of regulating erythropoiesis has not been completely delineated. Most of the studies were focused on the transcription factors to explore the mechanisms of erythropoiesis (4, 5). In recent years, several transcription factors were also identified to regulate definitive erythropoiesis in fetal liver during midgestation (6 -11). One of the transcription factors is ATF4, which has been shown to regulate cell proliferation in response to a broad spectrum of cell stresses and can be either an activator or a repressor in response to different extracellular signals (12). ATF4 Ϫ/Ϫ mice have been reported to cause defective definitive erythropoiesis, and severe anemia at midgestation (13). Although receptors, such as c-Kit and EPOR, have been well studied in erythropoiesis (14), little is known on the function of G-proteincoupled receptors (GPCRs) in erythropoiesis during development (14, 15).The GPCR family represents the largest and most versatile group of cell surface receptors (16 -18). GPCRs can recognize their ligands, a diverse array of extracellular signals, then transmit th...

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“…In erythrocytes and neuronal cells, EPO and EPO-R stimulation can activate protein kinase cascades (15,42,43). The primary kinase signaling pathway is the stress-responsive Jak2, which can lead to phosphorylation and activation of several downstream targets, including the transcription factor STAT5 (42).…”

Section: Discussionmentioning

confidence: 99%

“…The primary kinase signaling pathway is the stress-responsive Jak2, which can lead to phosphorylation and activation of several downstream targets, including the transcription factor STAT5 (42). Jak-STAT signaling is involved in prevention of neuronal apoptosis (15) and interestingly, the Jak-STAT pathway has recently been shown to play a role in cardiac ischemic preconditioning, thereby reducing ischemic damage to the heart (44).…”

Section: Discussionmentioning

confidence: 99%

A novel protective effect of erythropoietin in the infarcted heart

Parsa¹,

Matsumoto²,

Kim³

et al. 2003

J. Clin. Invest.

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Erythropoietin (EPO) has been shown to protect neurons from ischemic stroke, but can also increase thrombotic events and mortality rates in patients with ischemic heart disease. We reasoned that benefits of EPO might be offset by increases in hematocrit and evaluated the direct effects of EPO in the ischemic heart. We show that preconditioning with EPO protects H9c2 myoblasts in vitro and cardiomyocytes in vivo against ischemic injury. EPO treatment leads to significantly improved cardiac function following myocardial infarction. This protection is associated with mitigation of myocyte apoptosis, translating into more viable myocardium and less ventricular dysfunction. EPO-mediated myocyte survival appears to involve Akt activation. Importantly, cardioprotective effects of EPO were seen without an increase in hematocrit (eliminating oxygen delivery as an etiologic factor in myocyte survival and function), demonstrating that EPO can directly protect the ischemic and infarcted heart. Conflict of interest:The authors have declared that no conflict of interest exists. Nonstandard abbreviations used: myocardial infarction (MI); erythropoietin (EPO); erythropoietin receptor (EPO-R); Janus-associated kinase-2 (Jak2); trichloroacetic acid (TCA); left circumflex coronary artery (LCx); reactive oxygen species (ROS); left ventricle (LV); triphenyltetrazolium chloride (TTC); β-adrenergic receptor (βAR); LV end-diastolic pressure (LVEDP).

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Prostaglandin-E2 enhances EPO-mediated STAT5 transcriptional activity by serine phosphorylation of CREB

Cited by 51 publications

References 43 publications

Prostaglandin E2 Augments IL-10 Signaling and Function

Prostaglandin E2 Augments IL-10 Signaling and Function

Inactivation of G-protein-coupled Receptor 48 (Gpr48/Lgr4) Impairs Definitive Erythropoiesis at Midgestation through Down-regulation of the ATF4 Signaling Pathway

A novel protective effect of erythropoietin in the infarcted heart

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