ERB-041, a selective ERβ agonist, inhibits iNOS production in LPS-activated peritoneal macrophages of endometriosis via suppression of NF-κB activation

Physiologic activation of nuclear factor kappa-B in the endometrium during the menstrual cycle is altered in endometriosis patients

“…The cyclic p65-DNA binding pattern observed in this group of healthy women (increased binding in proliferative endometrium versus menstrual and secretory endometrium) is in agreement with works demonstrating NF-kB inhibition by progesterone (P) or progestational compounds in endometriotic stromal cells (27). Additionally, negative interaction between p65 and P receptor in other cell types (46) and antagonistic crosstalk with estrogen receptors (ER) in ESC and other cell types have been described (47)(48)(49)(50)(51)(52). Other authors had proposed that P inhibition of NF-kB activity during the secretory phase could be suppressed by P withdrawal, thereby increasing NF-kB activation during menstruation; but none of them directly and/or quantitatively studied NF-kB-DNA binding in menstrual endometrial tissue (17,35).…”

Involvement of the nuclear factor-κB pathway in the pathogenesis of endometriosis

“…Also, NF-kB activation significantly reduced estrogen responsiveness of ER-a-transfected ESCs, but p50 did not impair ER-a DNA binding, suggesting possible indirect mechanisms for this type of interaction (154). In peritoneal macrophages from endometriosis patients, ER-b agonist inhibits iNOS production, probably by repressing NF-kB (155).…”

“…Y IL-8 P, danazol, dienogest (63) In vitro, EcSC Y IL-8 IKK-2 inhibitor (64) In vitro, EcEC line Y IL-8, IL-6, MCP-1, GM-CSF, ICAM-1 and MMP-9 Y cell invasion Pioglitazone (88) In vitro, EcSC Y IL-8 and cell proliferation IL-10 (159) In vitro, EcSC Y IL-6 NF-kB decoy ODNs (68) In vitro, EcSC Y RANTES Y monocyte chemotactic activity BAY- 11-7085 (33, 87) In vitro, EcSC Y Bcl-2 and Bcl-XLn [ caspase-3, -9, and -8 activation In vivo, nude mouse a Y Ec lesion development Y cell proliferation and [ apoptosis Y ICAM-1 PDTC and bortezomib (138) In vivo, rat c Y Ec lesion development Y cell proliferation and angiogenesis CAPE (162) In vivo, rat c Y Ec lesion development Y oxidative stress Eicosapentanoic acid (163) In vivo, rat c Y inflammation Y PGES, MMP-13 and NF-kB Glycine (164) In vivo, hamster d No effect hCG (165,166) In vitro, EcSC Y IL-1b and TNF-a In vivo, human Y symptoms ERb agonist (155) In vitro, peritoneal Mo Y iNOS Note: Unless otherwise specified, in vitro studies were performed on human cells. Bcl ¼ B-cell lymphoma/leukemia; CAPE ¼ caffeic acid phenethyl ester; COX ¼ cyclooxygenase; EcEC ¼ endometriotic epithelial cells; EcSC ¼ endometriotic stromal cells; EEC ¼ endometrial epithelial cells; ER ¼ estrogen receptor; ESC ¼ endometrial stromal cells; GM-CSF ¼ granulocyte macrophage-colony-stimulating factor; GnRH-a, gonadotropin-releasing hormone agonist; hCG, human chorionic gonadotropin; ICAM, intercellular adhesion molecule; IKK ¼ IkB kinase; IL ¼ interleukin; iNOS ¼ inducible nitric oxide synthase; LIF ¼ leukemia inhibitory factor; MIF ¼ macrophage-migration inhibitory factor; MMP ¼ matrix metalloproteinase; Mo ¼ macrophages; ODNs ¼ decoy oligonucleotides; P ¼ progesterone; PDTC ¼ pyrrolidine dithiocarbamate; PGES ¼ prostaglandin E synthase, PTGS ¼ prostaglandinendoperoxide synthase; RANTES ¼ regulated upon activation, normal T-cell expressed and secreted; TNF-a ¼ tumor necrosis factor-a; TPCK ¼ N-tosyll-phenylalanine chloromethyl ketone.…”

Nudging oligodendrocyte intrinsic signaling to remyelinate and repair: Estrogen receptor ligand effects

“…IC 50 values are 5 and 1216 nM for human ERβ and ERα, 3.1 and 620 nM for rat ERβ and ERα, and 3.7 and 750 nM for mouse ERβ and ERα, respectively [109]. ERB-041 regulates hippocampal synaptic plasticity and memory improvement in gonadectomized mice [110] and exerts an anti-inflammatory effect in a lipopolysaccharide (LPS) model [54]. Clinically-relevant applications have included inflammatory bowel disease, rheumatoid arthritis, endometriosis, and sepsis [111, 112], but ERB-041 failed to improve EAE [113].…”

“…Additionally, preliminary in vivo data from our lab suggest that this ligand has the ability to modulate the peripheral immune response. Interestingly, while in vivo studies cited above indicate an immunomodulatory effect based on improved disease outcomes, the mechanisms of immune modulation appear to be at least partially distinct from Ind-Cl and similar to DPN in the inability to reduce iNOS production in LPS-stimulated microglia [54]. This suggests that the anti-inflammatory effects of ERB-041 are regulated through an alternate pathway and reinforces the view that anti-inflammatory effects of ERβ ligands are cell type-specific.…”