Expression pattern and signalling pathways in neutrophil like HL-60 cells after treatment with estrogen receptor selective ligands

Selvanesan, Blesson Chellakkan; Sahlin, Lena

doi:10.1016/j.mce.2012.04.006

Cited by 22 publications

(15 citation statements)

References 51 publications

(62 reference statements)

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“…We first found that AGs express GPER at both mRNA and protein levels and, more importantly, at much higher levels than other immune cells. To our knowledge, little is known regarding the expression of GPER in immune cells, and there is only one study describing the expression of GPER in neutrophil-like HL-60 cells (34). In our results, we also obtained a very low, but consistent, expression of GPER in G7 2 (AG-depleted) cell fractions.…”

Section: Discussionsupporting

confidence: 76%

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Estrogen Signaling through the G Protein–Coupled Estrogen Receptor Regulates Granulocyte Activation in Fish

Cabas

Rodenas

Abellán

et al. 2013

The Journal of Immunology

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Neutrophils are major participants in innate host responses. It is well known that estrogens have an immune-modulatory role, and some evidence exists that neutrophil physiology can be altered by these molecules. Traditionally, estrogens act via classical nuclear estrogen receptors, but the identification of a G protein–coupled estrogen receptor (GPER), a membrane estrogen receptor that binds estradiol and other estrogens, has opened up the possibility of exploring additional estrogen-mediated effects. However, information on the importance of GPER for immunity, especially, in neutrophils is scant. In this study, we report that gilthead seabream (Sparus aurata L.) acidophilic granulocytes, which are the functional equivalent of mammalian neutrophils, express GPER at both mRNA and protein levels. By using a GPER selective agonist, G1, it was found that GPER activation in vitro slightly reduced the respiratory burst of acidophilic granulocytes and drastically altered the expression profile of several genes encoding major pro- and anti-inflammatory mediators. In addition, GPER signaling in vivo modulated adaptive immunity. Finally, a cAMP analog mimicked the effects of G1 in the induction of the gene coding for PG-endoperoxide synthase 2 and in the induction of CREB phosphorylation, whereas pharmacological inhibition of protein kinase A superinduced PG-endoperoxide synthase 2. Taken together, our results demonstrate for the first time, to our knowledge, that estrogens are able to modulate vertebrate granulocyte functions through a GPER/cAMP/protein kinase A/CREB signaling pathway and could establish therapeutic targets for several immune disorders in which estrogens play a prominent role.

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Section: Discussionsupporting

confidence: 76%

“…These cells express ERa and ERb as well as their various splice variants (32,33). A recent study has shown that neutrophillike HL60 cells express a functional GPER (34). However, it is unknown whether primary neutrophils express GPER and, if this is the case, what its functional relevance in neutrophil biology is.…”

mentioning

confidence: 99%

Estrogen Signaling through the G Protein–Coupled Estrogen Receptor Regulates Granulocyte Activation in Fish

Cabas

Rodenas

Abellán

et al. 2013

The Journal of Immunology

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“…However, although there have been almost 900 publications on GPER1 since its discovery in the early 2000s and its expression in immune cells has been described [37], the in vivo role of GPER1 in the regulation of neutrophil function still remains enigmatic. The present study shows that GPER1 is functionally expressed in human neutrophils, extending a previous study reporting the functionality of this receptor in terminally differentiated neutrophil-like HL-60 cells [27]. Curiously, GPER1 expression was unaffected by neutrophil stimulation with different cytokines and LPS.…”

Section: Discussionsupporting

confidence: 87%

“…Thus, it has been described that estrogens are able to reduce superoxide anion release by human neutrophils [25,26]. More recently, it has been reported that terminally differentiated neutrophil-like HL-60 cells express functional ERα, ERβ, and GPER1 [27]. Therefore, in this study we sought to address the question of whether human neutrophils express a functional GPER1, using its specific agonist G1.…”

Section: Introductionmentioning

confidence: 99%

G Protein-Coupled Estrogen Receptor 1 Regulates Human Neutrophil Functions

et al. 2017

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Background: The role of estrogens in immune functioning is relatively well known under both physiological and pathological conditions. Neutrophils are the most abundant circulating leukocytes in humans, and their abundance and function are regulated by estrogens, since they express estrogen receptors (ERs). Traditionally, estrogens were thought to act via classical nuclear ERs, namely ERα and ERβ. However, it was observed that some estrogens induced biological effects only minutes after their application. This rapid, “nongenomic” effect of estrogens is mediated by a membrane-anchored receptor called G protein-coupled estrogen receptor 1 (GPER1). Nevertheless, the expression and role of GPER1 in the immune system has not been exhaustively studied, and its relevance in neutrophil functions remains unknown. Methods: Human neutrophils were incubated in vitro with 10-100 µM of the GPER1-specific agonist G1 alone or in combination with lipopolysaccharide. GPER1 expression and subcellular localization, respiratory burst, life span, gene expression profile, and cell signaling pathways involved were then analyzed in stimulated neutrophils. Results: Human neutrophils express a functional GPER1 which regulates their functions through cAMP/protein kinase A/cAMP response element-binding protein, p38 mitogen-activated protein kinase, and extracellular regulated MAPK signaling pathways. Thus, GPER1 activation in vitro increases the respiratory burst of neutrophils, extends their life span, and drastically alters their gene expression proﬁle. Conclusions: Our results demonstrate that GPER1 activation promotes the polarization of human neutrophils towards a proinflammatory phenotype and point to GPER1 as a potential therapeutic target in immune diseases where neutrophils play a key role.

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“…Estrogen-responsive genes have been identified by other groups through DNA microarray/genome-wide assays, where genes associated with signaling pathways, such as Wnt [119], cyclin D1 [120], JAK/STAT [121,122], G-protein-coupled estrogen receptor-1 (GPER1 or GPR30) [123], NF-κB [124] or IGF-2 [125] pathways, were identified. The genes identified are similar to those that we found, but are not identical, probably due to differences in the conditions of estrogen treatment (such as the origin of cells used, conditions in estrogen starvation of cells, the length of time for culturing cells and concentrations of chemicals) and/or in the microarray assays (such as the extraction protocol for mRNA, the design of probes on microarrays, the sensitivity of the detection of fluorescent signals and the methods of data analysis).…”

Section: Conclusion and Future Prospectsmentioning

confidence: 99%