PloS one, 2013-12, Vol.8 (12), p.e83072-e83072
2013
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- Autor(en) / Beteiligte
- Titel
- Estrogen-induced nongenomic calcium signaling inhibits lipopolysaccharide-stimulated tumor necrosis factor α production in macrophages
- Ist Teil von
- PloS one, 2013-12, Vol.8 (12), p.e83072-e83072
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2013
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- Estrogen is traditionally thought to exert genomic actions through members of the nuclear receptor family. Here, we investigated the rapid nongenomic effects of 17β-estradiol (E2) on tumor necrosis factor α (TNF-α) production following lipopolysaccharide (LPS) stimulation in mouse bone marrow-derived macrophages (BMMs). We found that LPS induced TNF-α production in BMMs via phosphorylation of p38 mitogen-activated protein kinase (MAPK). E2 itself did not affect the MAPK pathway, although it attenuated LPS-induced TNF-α production through suppression of p38 MAPK activation. Recently, G protein-coupled receptor 30 (GPR30) was suggested to be a membrane estrogen receptor (mER) that can mediate nongenomic estradiol signaling. We found that BMMs expressed both intracellular estrogen receptors (iER) and mER GPR30. The specific GPR30 antagonist G-15 significantly blocked effects of estradiol on LPS-induced TNF-α production, whereas an iER antagonist did not. Moreover, E2 induced a rapid rise in intracellular free Ca(2+) that was due to the influx of extracellular Ca(2+) and was not inhibited by an iER antagonist or silencing of iER. Ca(2+) influx was also induced by an impermeable E2 conjugated to BSA (E2-BSA), which has been used to investigate the nongenomic effects of estrogen. Consequently, Ca(2+), a pivotal factor in E2-stimulated nongenomic action, was identified as the key mediator. The inhibitory effects of E2 on LPS-induced TNF-α production and p38 MAPK phosphorylation were dependent on E2-triggered Ca(2+) influx because BAPTA, an intracellular Ca(2+) chelator, prevented these effects. Taken together, these data indicate that E2 can down-regulate LPS-induced TNF-α production via blockade of p38 MAPK phosphorylation through the mER-mediated nongenomic Ca(2+) signaling pathway in BMMs.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0083072Titel-ID: cdi_plos_journals_1470558581
- Format
- –
- Schlagworte
- 17β-Estradiol, Accreditation, Animals, Benzodioxoles - pharmacology, Bone marrow, Calcium, Calcium (extracellular), Calcium (intracellular), Calcium - metabolism, Calcium influx, Calcium Signaling - drug effects, Calcium signalling, Cytokines, Egtazic Acid - analogs & derivatives, Egtazic Acid - pharmacology, Endocrinology, Estradiol - pharmacology, Estrogen receptors, Estrogens, Forensic medicine, Gene Expression Regulation, Immune system, Intracellular, Intracellular signalling, Kinases, Laboratory animals, Lipopolysaccharides, Lipopolysaccharides - pharmacology, Macrophages, Macrophages - cytology, Macrophages - drug effects, Macrophages - metabolism, Male, MAP kinase, Mice, Mice, Inbred C57BL, Necrosis, p38 Mitogen-Activated Protein Kinases - genetics, p38 Mitogen-Activated Protein Kinases - metabolism, Pathology, Phosphorylation, Primary Cell Culture, Protein kinase, Proteins, Quinolines - pharmacology, Receptors, Receptors, Estrogen - antagonists & inhibitors, Receptors, Estrogen - genetics, Receptors, Estrogen - metabolism, Receptors, G-Protein-Coupled - antagonists & inhibitors, Receptors, G-Protein-Coupled - genetics, Receptors, G-Protein-Coupled - metabolism, Rheumatoid arthritis, Rodents, Serum Albumin, Bovine - pharmacology, Sex hormones, Signal transduction, Transcription factors, Trauma, Tumor Necrosis Factor-alpha - antagonists & inhibitors, Tumor Necrosis Factor-alpha - biosynthesis, Tumor Necrosis Factor-alpha - genetics, Tumor necrosis factor-TNF, Tumor necrosis factor-α