Anti-inflammatory effects of progesterone in lipopolysaccharide-stimulated BV-2 microglia.
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Female sex is associated with improved outcome in experimental brain injury models, such as traumatic brain injury, ischemic stroke, and intracerebral hemorrhage. This implies female gonadal steroids may be neuroprotective. A mechanism for this may involve modulation of post-injury neuroinflammation. As the resident immunomodulatory cells in central nervous system, microglia are activated during acute brain injury and produce inflammatory mediators which contribute to secondary injury including proinflammatory cytokines, and nitric oxide (NO) and prostaglandin E2 (PGE2), mediated by inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2), respectively. We hypothesized that female gonadal steroids reduce microglia mediated neuroinflammation. In this study, the progesterone's effects on tumor necrosis factor alpha (TNF-α), iNOS, and COX-2 expression were investigated in lipopolysaccharide (LPS)-stimulated BV-2 microglia. Further, investigation included nuclear factor kappa B (NF-κB) and mitogen activated protein kinase (MAPK) pathways. LPS (30 ng/ml) upregulated TNF-α, iNOS, and COX-2 protein expression in BV-2 cells. Progesterone pretreatment attenuated LPS-stimulated TNF-α, iNOS, and COX-2 expression in a dose-dependent fashion. Progesterone suppressed LPS-induced NF-κB activation by decreasing inhibitory κBα and NF-κB p65 phosphorylation and p65 nuclear translocation. Progesterone decreased LPS-mediated phosphorylation of p38, c-Jun N-terminal kinase and extracellular regulated kinase MAPKs. These progesterone effects were inhibited by its antagonist mifepristone. In conclusion, progesterone exhibits pleiotropic anti-inflammatory effects in LPS-stimulated BV-2 microglia by down-regulating proinflammatory mediators corresponding to suppression of NF-κB and MAPK activation. This suggests progesterone may be used as a potential neurotherapeutic to treat inflammatory components of acute brain injury.
Drug Evaluation, Preclinical
Extracellular Signal-Regulated MAP Kinases
Nitric Oxide Synthase Type II
Protein Processing, Post-Translational
Tumor Necrosis Factor-alpha
Published Version (Please cite this version)10.1371/journal.pone.0103969
Publication InfoLei, Beilei; Mace, Brian; Dawson, Hana N; Warner, David S; Laskowitz, Daniel T; & James, Michael L (2014). Anti-inflammatory effects of progesterone in lipopolysaccharide-stimulated BV-2 microglia. PLoS One, 9(7). pp. e103969. 10.1371/journal.pone.0103969. Retrieved from https://hdl.handle.net/10161/14241.
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Adjunct Assistant Professor in the Department of Neurology
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Associate Professor of Anesthesiology
I have an extensive background in neuroanesthesia and neurointensive care and a special research interest in translational and clinical research aspects of intracerebral hemorrhage. After completing residencies in neurology and anesthesiology with fellowships in neurocritical care, neuroanesthesia, and vascular neurology, I developed a murine model of intracerebral hemorrhage in the Multidisciplinary Neuroprotection Laboratories at Duke University. After optimization of the model, I h
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Our laboratory uses molecular biology, cell culture, and animal modeling techniques to examine the CNS response to acute injury. In particular, our laboratory examines the role of microglial activation and the endogenous CNS inflammatory response in exacerbating secondary injury following acute brain insult. Much of the in vitro work in this laboratory is dedicated to elucidating cellular responses to injury with the ultimate goal of exploring new therapeutic interventions in the clinical settin
Distinguished Distinguished Professor of Anesthesiology, in the School of Medicine
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