title: Estrogen anti-inflammatory activity on human monocytes is mediated through cross-talk between estrogen receptor ERα36 and GPR30/GPER1.
abstract: Estrogens are known modulators of monocyte/macrophage functions; however, the underlying mechanism has not been clearly defined. Recently, a number of estrogen receptor molecules and splice variants were identified that exert different and sometimes opposing actions. We assessed the expression of estrogen receptors and explored their role in mediating estrogenic anti-inflammatory effects on human primary monocytes. We report that the only estrogen receptors expressed are estrogen receptor-α 36-kDa splice variant and G-protein coupled receptor 30/G-protein estrogen receptor 1, in a sex-independent manner. 17-β-Estradiol inhibits the LPS-induced IL-6 inflammatory response, resulting in inhibition of NF-κB transcriptional activity. This is achieved via a direct physical interaction of ligand-activated estrogen receptor-α 36-kDa splice variant with the p65 component of NF-κB in the nucleus. G-protein coupled receptor 30/G-protein estrogen receptor 1, which also physically interacts with estrogen receptor-α 36-kDa splice variant, acts a coregulator in this process, because its inhibition blocks the effect of estrogens on IL-6 expression. However, its activation does not mimic the effect of estrogens, on neither IL-6 nor NF-κB activity. Finally, we show that the estrogen receptor profile observed in monocytes is not modified during their differentiation to macrophages or dendritic cells in vitro and is shared in vivo by macrophages present in atherosclerotic plaques. These results position estrogen receptor-α 36-kDa splice variant and G-protein coupled receptor 30 as important players and potential therapeutic targets in monocyte/macrophage-dependent inflammatory processes.
authors.affiliation: Laboratories of *Experimental Endocrinology, Pathology, and Biochemistry, University of Crete School of Medicine, Heraklion, Crete, Greece; First Department of Pathology, National and Kapodistrian University of Athens School of Medicine, Athens, Greece; INSERM U976, Hôpital Saint Louis, Paris, France; and University Paris Diderot, Paris, France.
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Pelekanou
authors.affiliation: Laboratories of *Experimental Endocrinology, Pathology, and Biochemistry, University of Crete School of Medicine, Heraklion, Crete, Greece; First Department of Pathology, National and Kapodistrian University of Athens School of Medicine, Athens, Greece; INSERM U976, Hôpital Saint Louis, Paris, France; and University Paris Diderot, Paris, France.
authors.forename: Marilena
authors.initials: M
authors.lastname: Kampa
authors.affiliation: Laboratories of *Experimental Endocrinology, Pathology, and Biochemistry, University of Crete School of Medicine, Heraklion, Crete, Greece; First Department of Pathology, National and Kapodistrian University of Athens School of Medicine, Athens, Greece; INSERM U976, Hôpital Saint Louis, Paris, France; and University Paris Diderot, Paris, France.
authors.forename: Foteini
authors.initials: F
authors.lastname: Kiagiadaki
authors.affiliation: Laboratories of *Experimental Endocrinology, Pathology, and Biochemistry, University of Crete School of Medicine, Heraklion, Crete, Greece; First Department of Pathology, National and Kapodistrian University of Athens School of Medicine, Athens, Greece; INSERM U976, Hôpital Saint Louis, Paris, France; and University Paris Diderot, Paris, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Deli
authors.affiliation: Laboratories of *Experimental Endocrinology, Pathology, and Biochemistry, University of Crete School of Medicine, Heraklion, Crete, Greece; First Department of Pathology, National and Kapodistrian University of Athens School of Medicine, Athens, Greece; INSERM U976, Hôpital Saint Louis, Paris, France; and University Paris Diderot, Paris, France.
authors.forename: Panayiotis
authors.initials: P
authors.lastname: Theodoropoulos
authors.affiliation: Laboratories of *Experimental Endocrinology, Pathology, and Biochemistry, University of Crete School of Medicine, Heraklion, Crete, Greece; First Department of Pathology, National and Kapodistrian University of Athens School of Medicine, Athens, Greece; INSERM U976, Hôpital Saint Louis, Paris, France; and University Paris Diderot, Paris, France.
authors.forename: George
authors.initials: G
authors.lastname: Agrogiannis
authors.affiliation: Laboratories of *Experimental Endocrinology, Pathology, and Biochemistry, University of Crete School of Medicine, Heraklion, Crete, Greece; First Department of Pathology, National and Kapodistrian University of Athens School of Medicine, Athens, Greece; INSERM U976, Hôpital Saint Louis, Paris, France; and University Paris Diderot, Paris, France.
authors.forename: Efstratios
authors.initials: E
authors.lastname: Patsouris
authors.affiliation: Laboratories of *Experimental Endocrinology, Pathology, and Biochemistry, University of Crete School of Medicine, Heraklion, Crete, Greece; First Department of Pathology, National and Kapodistrian University of Athens School of Medicine, Athens, Greece; INSERM U976, Hôpital Saint Louis, Paris, France; and University Paris Diderot, Paris, France.
authors.forename: Andreas
authors.initials: A
authors.lastname: Tsapis
authors.affiliation: Laboratories of *Experimental Endocrinology, Pathology, and Biochemistry, University of Crete School of Medicine, Heraklion, Crete, Greece; First Department of Pathology, National and Kapodistrian University of Athens School of Medicine, Athens, Greece; INSERM U976, Hôpital Saint Louis, Paris, France; and University Paris Diderot, Paris, France.
authors.forename: Elias
authors.initials: E
authors.lastname: Castanas
authors.affiliation: Laboratories of *Experimental Endocrinology, Pathology, and Biochemistry, University of Crete School of Medicine, Heraklion, Crete, Greece; First Department of Pathology, National and Kapodistrian University of Athens School of Medicine, Athens, Greece; INSERM U976, Hôpital Saint Louis, Paris, France; and University Paris Diderot, Paris, France gnotas@med.uoc.gr.
authors.forename: George
authors.initials: G
authors.lastname: Notas
mesh_terms: D000368:Aged; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D003324:Coronary Artery Disease / Q000473:pathology; D003713:Dendritic Cells / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000737:chemistry / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D005260:Female; D005487:Foam Cells / Q000378:metabolism / Q000473:pathology; D000077267:Fulvestrant; D017930:Genes, Reporter; D006801:Humans; D007249:Inflammation; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D038042:Myelopoiesis; D025941:Protein Interaction Mapping; D020033:Protein Isoforms / Q000737:chemistry / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D020239:Receptor Cross-Talk / Q000502:physiology*; D011960:Receptors, Estrogen / Q000737:chemistry / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000502:physiology*; D051996:Transcription Factor RelA / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000893:Anti-Inflammatory Agents; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C109584:GPER1 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D008070:Lipopolysaccharides; D020033:Protein Isoforms; C498143:RELA protein, human; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D051996:Transcription Factor RelA; D000077267:Fulvestrant; D004958:Estradiol
keywords: IL-6; NF-κB; atherosclerosis; macrophages