Evidence for a regulatory role of α4 – integrins in the maturation of eosinophils generated from the bone marrow in the presence of dexamethasone

Gaspar−Elsas, Maria Ignez C.; Queto, Túlio; Vasconcelos, Zilton; Jones, Carla P.; Lannes‐Vieira, Joseli; Xavier−Elsas, Pedro

doi:10.1111/j.1365-2222.2009.03289.x

Cited by 19 publications

(39 citation statements)

References 33 publications

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“…This hypothesis would be consistent with the observation that G-CSF only affected eosinophils in challenged animals, which generate this signal, unlike unchallenged controls (Gaspar Elsas et al 1997). Following our original demonstration by transfer experiments (Gaspar Elsas et al 1997), a number of defined stimuli have been shown to upregulate eosinophil production in vivo and in vitro, including glucocorticoids, either exogenously administered (Gaspar- Elsas et al 2009) or endogenously released from the adrenal glands of surgically stressed mice (Elsas et al 2004). However, while glucocorticoid-induced eosinophilopoiesis has been shown to be blocked by the glucocorticoid receptor antagonist, RU486 (mifepristone) (Gaspar- Elsas et al 2009), the nature of the mediator induced by allergen challenge remains undefined.…”

Section: Discussionmentioning

confidence: 97%

“…Following our original demonstration by transfer experiments (Gaspar Elsas et al 1997), a number of defined stimuli have been shown to upregulate eosinophil production in vivo and in vitro, including glucocorticoids, either exogenously administered (Gaspar- Elsas et al 2009) or endogenously released from the adrenal glands of surgically stressed mice (Elsas et al 2004). However, while glucocorticoid-induced eosinophilopoiesis has been shown to be blocked by the glucocorticoid receptor antagonist, RU486 (mifepristone) (Gaspar- Elsas et al 2009), the nature of the mediator induced by allergen challenge remains undefined. G-CSF, the first immunomodulatory cytokine able to prevent the effects of allergen challenge on bone-marrow eosinophilopoiesis, may either prevent the generation of this systemic mediator, or interfere with its activity.…”

Section: Discussionmentioning

confidence: 97%

“…Briefly, 10 6 bone-marrow cells were seeded in 1 ml of RPMI 1640 medium, with 10% FCS, in the presence of rmIL-5 (1 ng/ml), or rmGM-CSF (1 ng/ml) and incubated at 37°C, 5% CO2/95% air for 7 (for eosinophils) or 6 (for neutrophils) days. Cells were resuspended, counted, cytocentrifuged and stained (for eosinophils, for eosinophil peroxidase, or EPO, with counterstaing by Harris' Hematoxylin (Ten et al 1989); for neutrophils, Wright-Giemsa (Gaspar- Elsas et al 2009), before differential counts. We have previously reported that: a) EPO-staining closely matches immunostaining for CCR3 and WrightGiemsa staining (Gaspar- Elsas et al 2009); and b) these culture conditions support eosinophil proliferation and terminal differentiation, allowing detection of both enhancing (Gaspar- Elsas et al 2000a) and suppressive (Gaspar-Elsas et al 2000b) effects.…”

Section: Hematological Proceduresmentioning

confidence: 99%

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G-CSF suppresses allergic pulmonary inflammation, downmodulating cytokine, chemokine and eosinophil production

et al. 2011

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 97%

Section: Hematological Proceduresmentioning

confidence: 99%

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G-CSF suppresses allergic pulmonary inflammation, downmodulating cytokine, chemokine and eosinophil production

et al. 2011

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“…At the cellular level and in murine allergic inflammation, PGE 2 was found to inhibit eosinophil trafficking via EP2 receptor activation [18]. In mouse BM, PGE 2 decreased the number of eosinophil peroxidase-positive cells and reduced the expression of a4 integrin in eosinophils [19]. The role of PGE 2 in endothelial function has not been investigated in detail.…”

Section: Introductionmentioning

confidence: 99%

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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“…At the initiation of implantation, expression of Itga4 is induced in the uterus, and in vivo blocking of Itga4 in the uterus of pregnant mice on the day of implantation leads to implantation failure (13). Dexamethasone has been shown to induce Itga4 expression in eosinophils and bonemarrow cultures, although to our knowledge this is the first study implicating GR regulation of Itga4 in the uterus during pregnancy (18). In addition to Itga4, many other plasma membrane receptors exhibited altered expression levels in uterine GR KO mice.…”

Section: Discussionmentioning

confidence: 61%

Uterine glucocorticoid receptors are critical for fertility in mice through control of embryo implantation and decidualization

Whirledge

Oakley

Myers

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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In addition to the well-characterized role of the sex steroid receptors in fertility and reproduction, organs of the female reproductive tract are also regulated by the hypothalamic-pituitary-adrenal axis. These endocrine organs are sensitive to stress-mediated actions of glucocorticoids, and the mouse uterus contains high levels of the glucocorticoid receptor (GR). Although the presence of GR in the uterus is well established, uterine glucocorticoid signaling has been largely ignored in terms of its reproductive and/or immunomodulatory functions on fertility. To define the direct in vivo function of glucocorticoid signaling in adult uterine physiology, we generated a uterine-specific GR knockout (uterine GR KO) mouse using the PR cre mouse model. The uterine GR KO mice display a profound subfertile phenotype, including a significant delay to first litter and decreased pups per litter. Early defects in pregnancy are evident as reduced blastocyst implantation and subsequent defects in stromal cell decidualization, including decreased proliferation, aberrant apoptosis, and altered gene expression. The deficiency in uterine GR signaling resulted in an exaggerated inflammatory response to induced decidualization, including altered immune cell recruitment. These results demonstrate that GR is required to establish the necessary cellular context for maintaining normal uterine biology and fertility through the regulation of uterine-specific actions.glucocorticoid receptor | uterus | decidualization | implantation

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Evidence for a regulatory role of α4 – integrins in the maturation of eosinophils generated from the bone marrow in the presence of dexamethasone

Abstract: These observations support a novel role for alpha 4 integrin receptors and ligands in eosinophilopoiesis. In addition, increased alpha 4 expression following glucocorticoid exposure may contribute to the retention and accumulation of eosinophils in haemopoietic tissue.

Cited by 19 publications

References 33 publications

G-CSF suppresses allergic pulmonary inflammation, downmodulating cytokine, chemokine and eosinophil production

G-CSF suppresses allergic pulmonary inflammation, downmodulating cytokine, chemokine and eosinophil production

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

Uterine glucocorticoid receptors are critical for fertility in mice through control of embryo implantation and decidualization

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