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      Anti-Inflammatory Effects of Progesterone in Lipopolysaccharide-Stimulated BV-2 Microglia

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          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 E 2 (PGE 2), 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.

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          Most cited references 52

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          Shared principles in NF-kappaB signaling.

          The transcription factor NF-kappaB has served as a standard for inducible transcription factors for more than 20 years. The numerous stimuli that activate NF-kappaB, and the large number of genes regulated by NF-kappaB, ensure that this transcription factor is still the subject of intense research. Here, we attempt to synthesize some of the basic principles that have emerged from studies of NF-kappaB, and we aim to generate a more unified view of NF-kappaB regulation.
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            Microglia-mediated neurotoxicity: uncovering the molecular mechanisms.

            Mounting evidence indicates that microglial activation contributes to neuronal damage in neurodegenerative diseases. Recent studies show that in response to certain environmental toxins and endogenous proteins, microglia can enter an overactivated state and release reactive oxygen species (ROS) that cause neurotoxicity. Pattern recognition receptors expressed on the microglial surface seem to be one of the primary, common pathways by which diverse toxin signals are transduced into ROS production. Overactivated microglia can be detected using imaging techniques and therefore this knowledge offers an opportunity not only for early diagnosis but, importantly, for the development of targeted anti-inflammatory therapies that might slow or halt the progression of neurodegenerative disease.
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              Regulation and function of NF-kappaB transcription factors in the immune system.

              The mammalian Rel/NF-kappaB family of transcription factors, including RelA, c-Rel, RelB, NF-kappaB1 (p50 and its precursor p105), and NF-kappaB2 (p52 and its precursor p100), plays a central role in the immune system by regulating several processes ranging from the development and survival of lymphocytes and lymphoid organs to the control of immune responses and malignant transformation. The five members of the NF-kappaB family are normally kept inactive in the cytoplasm by interaction with inhibitors called IkappaBs or the unprocessed forms of NF-kappaB1 and NF-kappaB2. A wide variety of signals emanating from antigen receptors, pattern-recognition receptors, receptors for the members of TNF and IL-1 cytokine families, and others induce differential activation of NF-kappaB heterodimers. Although work over the past two decades has shed significant light on the regulation of NF-kappaB transcription factors and their functions, much progress has been made in the past two years revealing new insights into the regulation and functions of NF-kappaB. This recent progress is covered in this review.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                31 July 2014
                : 9
                : 7
                Affiliations
                [1 ]Multidisciplinary Neuroprotection Laboratories, Duke University Medical Center, Durham, North Carolina, United States of America
                [2 ]Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina, United States of America
                [3 ]Department of Neurology, Duke University Medical Center, Durham, North Carolina, United States of America
                [4 ]Department of Neurobiology, Duke University Medical Center, Durham, North Carolina, United States of America
                National Institute of Allergy and Infectious Diseases - Rocky Mountain Laboratories, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: BL MLJ. Performed the experiments: BL BM. Analyzed the data: BL BM MLJ. Contributed reagents/materials/analysis tools: HND DSW DTL MLJ. Contributed to the writing of the manuscript: BL HND DSW DTL MLJ.

                Article
                PONE-D-14-14610
                10.1371/journal.pone.0103969
                4117574
                25080336

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Pages: 7
                Funding
                This work was supported by American Heart Association-Scientist Development Grant (MLJ). The funders had no role in study design, data collection and analysis, decision to publish, or prearation of the manuscript.
                Categories
                Research Article
                Biology and life sciences
                Biochemistry
                Neurochemistry
                Neurochemicals
                Nitric Oxide
                Neuroendocrinology
                Neuromodulation
                Cell biology
                Cell Physiology
                Cell Activation
                Cellular Types
                Animal Cells
                Glial Cells
                Microglial Cells
                Signal transduction
                Cell signaling
                Signaling cascades
                MAPK signaling cascades
                Immunological Signaling
                Molecular Cell Biology
                Developmental Biology
                Molecular Development
                Cytokines
                Immunology
                Immune System
                Innate Immune System
                Neuroimmunology
                Neuroscience
                Molecular Neuroscience
                Medicine and health sciences
                Neurology
                Cerebral Ischemia
                Pain management
                Analgesics
                COX-2 inhibitors
                Vascular Medicine
                Stroke
                Custom metadata
                The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files.

                Uncategorized

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