title: Estrogen attenuates lipopolysaccharide-induced nitric oxide production in macrophages partially via the nongenomic pathway.
abstract: Steroid hormones exert genotropic effects through members of the nuclear hormone receptor family. In the present study, we examined the effects of 17β-estradiol (E2) on nitric oxide (NO) production following lipopolysaccharide (LPS) stimulation and investigated the mechanisms in mouse bone marrow-derived macrophages (BMMs). E2 alone did not affect NO production. In contrast, E2 inhibited LPS-induced production of NO in BMMs. Using a cell-impermeable E2 conjugated to BSA (E2-BSA), which has been used to investigate the nongenomic effects of estrogen, we found that the increase in NO production induced by LPS was also attenuated. In addition, the intracellular estrogen receptor blocker, ICI 182780, only partially antagonized the total effects of E2 on LPS-stimulated NO production capacity. E2 also attenuated the LPS activation of p38 mitogen-activated protein kinase (MAPK) but not that of extracellular-regulated protein kinase 1/2 (ERK1/2) and c-Jun NH2-terminal kinase (JNK). This attenuation was not abrogated by ICI 182780. Moreover, the p38 inhibitor, SB 203580, greatly reduced the LPS-induced NO production, and the remaining NO levels were no longer regulated by E2. Additionally, E2-BSA inhibited LPS-mediated changes in p38 MAPK activation to the same extent as E2. Moreover, E2 and E2-BSA inhibited LPS-induced activation of nuclear factor-kappa B (NF-κB) and activator protein 1 (AP-1). This inhibitory effect of E2 was only partially antagonized by ICI 182780. Taken together, these results suggest that E2 has an inhibitory effect on LPS-induced NO production in BMMs through inhibition of p38 MAPK phosphorylation, and blockade of NF-κB and AP-1 activation. These effects are mediated at least in part via a nongenomic pathway.
authors: Departments of Pathology and Pathophysiology, Medical College of Soochow University, Suzhou 215123, Jiangsu, China.
authors: Limin
authors: L
authors: Liu
authors: Department of Forensic Medicine, Medical College of Soochow University, Suzhou 215123, Jiangsu, China. Electronic address: zufengwang@suda.edu.cn.
authors: Zufeng
authors: Z
authors: Wang
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology*; D020847:Estrogen Receptor Modulators / Q000494:pharmacology; D000077267:Fulvestrant; D015870:Gene Expression / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012710:Serum Albumin, Bovine / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D020847:Estrogen Receptor Modulators; D007093:Imidazoles; D008070:Lipopolysaccharides; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D018808:Transcription Factor AP-1; C043090:estradiol-bovine serum albumin; D000077267:Fulvestrant; D012710:Serum Albumin, Bovine; D009569:Nitric Oxide; D004958:Estradiol; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580
keywords: 17β-estradiol; AP-1; BMMs; E(2); E(2) conjugated to bovine serum albumin; E(2)–BSA; ERK1/2; Estrogen; IκB; JNK; LPS; MAPK; Macrophage; NF-κB; NO; Nitric oxide; Nongenomic pathway; activator protein 1; bone marrow-derived macrophages; c-Jun NH(2)-terminal kinase; extracellular-regulated protein kinase 1/2; iER; inhibitory kappa B; intracellular estrogen receptors; lipopolysaccharide; mER; membrane estrogen receptors; mitogen-activated protein kinase; nitric oxide; nuclear factor-kappa B