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      Poly(I:C) increases the expression of mPGES-1 and COX-2 in rat primary microglia

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          Abstract

          Background

          Microglia recognize pathogen-associated molecular patterns such as double-stranded RNA (dsRNA) present in some viruses. Polyinosinic-polycytidylic acid [poly(I:C)] is a synthetic analog of dsRNA that activates different molecules, such as retinoic acid-inducible gene I, melanoma differentiation-associated gene 5, and toll-like receptor-3 (TLR3). Poly(I:C) increases the expression of different cytokines in various cell types. However, its role in the regulation of the production of inflammatory mediators of the arachidonic acid pathway by microglia is poorly understood.

          Methods

          In the present study, we evaluated the effect of poly(I:C) on the production of prostaglandin E 2 (PGE 2) and the inducible enzymes cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1) in primary rat microglia. Microglia were stimulated with different concentrations of poly(I:C) (0.1–10 μg/ml), and the protein levels of COX-2 and mPGES-1, as well as the release of PGE 2, were determined by western blot and enzyme immunoassay (EIA), respectively. Values were compared using one-way ANOVA with post hoc Student-Newman-Keuls test.

          Results

          Poly(I:C) increased the production of PGE 2, as well as mPGES-1 and COX-2 synthesis. To investigate the mechanisms involved in poly(I:C)-induced COX-2 and mPGES-1, we studied the effects of various signal transduction pathway inhibitors. Protein levels of COX-2 and mPGES-1 were reduced by SB203580, SP600125, and SC514 (p38 mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK), and IκB kinase (IKK) inhibitors, respectively), as well as by PD98059 and PD0325901 (mitogen-activated protein kinase kinase (MEK) inhibitors). Rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, enhanced the synthesis of COX-2. Inhibition of phosphatidylinositol 3-kinase (PI3K) by LY294002 or dual inhibition of PI3K/mTOR (with NVP-BEZ235) enhanced COX-2 and reduced mPGES-1 immunoreactivity. To confirm the data obtained with the inhibitors, we studied the phosphorylation of the blocked kinases by western blot. Poly(I:C) increased the phosphorylation of p38 MAPK, extracellular signal-regulated kinase (ERK), JNK, protein kinase B (Akt), and IκB.

          Conclusions

          Taken together, our data demonstrate that poly(I:C) increases the synthesis of enzymes involved in PGE 2 synthesis via activation of different signaling pathways in microglia. Importantly, poly(I:C) activates similar pathways also involved in TLR4 signaling that are important for COX-2 and mPGES-1 synthesis. Thus, these two enzymes and their products might contribute to the neuropathological effects induced in response to dsRNA, whereby the engagement of TLR3 might be involved.

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          Most cited references52

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          Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism.

          Inflammation, a common denominator among the diverse list of neurodegenerative diseases, has recently been implicated as a critical mechanism responsible for the progressive nature of neurodegeneration. Microglia are the resident innate immune cells in the central nervous system and produce a barrage of factors (IL-1, TNFalpha, NO, PGE2, superoxide) that are toxic to neurons. Evidence supports that the unregulated activation of microglia in response to environmental toxins, endogenous proteins, and neuronal death results in the production of toxic factors that propagate neuronal injury. In the following review, we discuss the common thread of microglial activation across numerous neurodegenerative diseases, define current perceptions of how microglia are damaging neurons, and explain how the microglial response to neuronal damage results in a self-propelling cycle of neuron death.
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            Toll-like receptors in neurodegeneration.

            The key roles of toll-like receptors (TLRs) as mediators of the detection and responses of immune cells to invading pathogens are well known. There are at least 13 mammalian TLRs which are integral membrane proteins with a leucine-rich extracellular domain and a cytoplasmic domain similar to that of the interleukin-1 receptor which initiates downstream signaling through kinases to activate transcription factors such as AP-1 and NFkappaB. TLRs are activated in glial cells (microglia, astrocytes and oligodendrocytes) and lymphocytes that infiltrate the nervous system in response to inflammation caused by infectious agents, tissue injury or autoimmune conditions. By inducing the production of pro-inflammatory cytokines and cell adhesion molecules in immune cells, TLRs may indirectly damage neurons in conditions such as ischemic stroke and multiple sclerosis. Recent findings suggest that neurons also express a subset of TLRs and that their activation promotes neuronal degeneration in experimental models of stroke and Alzheimer's disease. TLRs may also play roles in regulating the processes of neurogenesis and neurite outgrowth, suggesting roles in neuronal plasticity. A better understanding of the molecular and cellular biology of TLRs in the normal and diseased nervous system, may lead to novel approaches for preventing neuronal degeneration and promoting recovery of function in an array of neurodegenerative conditions.
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              Emerging role of Toll-like receptors in the control of pain and itch.

              Toll-like receptors (TLRs) are germline-encoded pattern-recognition receptors that initiate innate immune responses by recognizing molecular structures shared by a wide range of pathogens, known as pathogen-associated molecular patterns (PAMPs). After tissue injury or cellular stress, TLRs also detect endogenous ligands known as danger-associated molecular patterns (DAMPs). TLRs are expressed in both non-neuronal and neuronal cell types in the central nervous system (CNS) and contribute to both infectious and non-infectious disorders in the CNS. Following tissue insult and nerve injury, TLRs (such as TLR2, TLR3, and TLR4) induce the activation of microglia and astrocytes and the production of the proinflammatory cytokines in the spinal cord, leading to the development and maintenance of inflammatory pain and neuropathic pain. In particular, primary sensory neurons, such as nociceptors, express TLRs (e.g., TLR4 and TLR7) to sense exogenous PAMPs and endogenous DAMPs released after tissue injury and cellular stress. These neuronal TLRs are new players in the processing of pain and itch by increasing the excitability of primary sensory neurons. Given the prevalence of chronic pain and itch and the suffering of affected people, insights into TLR signaling in the nervous system will open a new avenue for the management of clinical pain and itch.
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                Author and article information

                Contributors
                +55 (31)3409-2727 , antoniooliveira@icb.ufmg.br
                (49) 761/270-6898 , bernd.fiebich@uniklinik-freiburg.de
                Journal
                J Neuroinflammation
                J Neuroinflammation
                Journal of Neuroinflammation
                BioMed Central (London )
                1742-2094
                18 January 2016
                18 January 2016
                2016
                : 13
                : 11
                Affiliations
                [ ]Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Av. Antonio Carlos 6627, 31270-901 Belo Horizonte, MG Brazil
                [ ]Department of Psychiatry, University of Freiburg Medical School, Hauptstr. 5, 79104 Freiburg, Germany
                [ ]Zentrum für Geriatrie und Gerontologie, Sektion Gerontopsychiatrie und Neuropsychologie, Universitätsklinikums Freiburg, Lehener Str. 88, 79106 Freiburg, Germany
                [ ]Clinic for Geriatric Psychiatry, Center for Psychiatry Emmendingen, Neubronnstraße 25, 79312 Emmendingen, Germany
                [ ]VivaCell Biotechnology GmbH, Ferdinand-Porsche-Str. 5, 79211 Denzlingen, Germany
                Article
                473
                10.1186/s12974-015-0473-7
                4717620
                26780827
                37b11630-bb4d-4c2f-8ce3-2e580918d9e7
                © de Oliveira et al. 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 2 June 2015
                : 28 December 2015
                Funding
                Funded by: Alzheimer Forschung initiative e.V (AFI)
                Award ID: Pilot grant #13852
                Award Recipient :
                Funded by: Alzheimer Forschung initiative e.V (AFI)
                Award ID: Standard grant #10812
                Award Recipient :
                Funded by: State Law on Graduate Funding (LGFG-IGA, Freiburg)
                Award ID: Scholarship
                Award Recipient :
                Funded by: Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG)
                Award ID: PPM-00372-13
                Award Recipient :
                Funded by: Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
                Award ID: 479254/2013-3
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2016

                Neurosciences
                polyinosinic-polycytidylic acid,tlr3,cox-2,mpges-1,microglia
                Neurosciences
                polyinosinic-polycytidylic acid, tlr3, cox-2, mpges-1, microglia

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