Anti-inflammatory effects of progesterone in lipopolysaccharide-stimulated BV-2 microglia.
Abstract
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.
Type
Journal articleSubject
AnimalsAnti-Inflammatory Agents
Cell Line
Cyclooxygenase 2
Drug Evaluation, Preclinical
Extracellular Signal-Regulated MAP Kinases
Female
Lipopolysaccharides
Mice
Microglia
NF-kappa B
Nitric Oxide Synthase Type II
Phosphorylation
Progesterone
Protein Processing, Post-Translational
Protein Transport
Receptors, Progesterone
Tumor Necrosis Factor-alpha
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https://hdl.handle.net/10161/14241Published Version (Please cite this version)
10.1371/journal.pone.0103969Publication Info
Lei, 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.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Hana Nenicka Dawson
Adjunct Assistant Professor in the Department of Neurology
Our laboratory studies the role of tau protein in neurodegeneration. Aggregated tau
protein is a hallmark feature of a group of neurodegenerative dementias called tauopathies.
This group of diseases accounts for a large majority of all dementias and includes
Alzheimer's disease, Pick's disease and frontotemporal dementia to name a few. To
model tauopathies, we overexpressed normal and mutated human tau protein or no tau
protein in the central nervous system of transgenic mice. Several of t
Michael Lucas James
Professor of Anesthesiology
With a clinical background in neuroanesthesia and neurointensive care, I have a special
interest in translational research in intracerebral hemorrhage and traumatic brain
injury. I am fortunate to be part of a unique team of highly motivated and productive
individuals who allow me to propel ideas from bench to bedside and the ability to
reverse translate ideas from the bedside back to the bench.
Daniel Todd Laskowitz
Professor of Neurology
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
David Samuel Warner
Distinguished Distinguished Professor of Anesthesiology, in the School of Medicine
Humans may sustain a variety of forms of acute central nervous system injury including
ischemia, trauma, vasospasm, and perinatal hypoxemia. The Multidisciplinary Neuroprotection
Laboratories is dedicated to examining the pathophysiology of acute brain and spinal
cord injury with particular reference to disease states managed in the perioperative
or neurointensive care environments. Rodent recovery models of cerebral ischemia,
traumatic brain injury, cardiopulmonary bypass, subarachnoid he
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