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      Exercise attenuates neurological deficits by stimulating a critical HSP70/NF-κB/IL-6/synapsin I axis in traumatic brain injury rats

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          Abstract

          Background

          Despite previous evidence for a potent inflammatory response after a traumatic brain injury (TBI), it is unknown whether exercise preconditioning (EP) improves outcomes after a TBI by modulating inflammatory responses.

          Methods

          We performed quantitative real-time PCR (qPCR) to quantify the genes encoding 84 cytokines and chemokines in the peripheral blood and used ELISA to determine both the cerebral and blood levels of interleukin-6 (IL-6). We also performed the chromatin immunoprecipitation (ChIP) assay to evaluate the extent of nuclear factor kappa-B (NF-κB) binding to the DNA elements in the IL-6 promoter regions. Also, we adopted the Western blotting assay to measure the cerebral levels of heat shock protein (HSP) 70, synapsin I, and β-actin. Finally, we performed both histoimmunological and behavioral assessment to measure brain injury and neurological deficits, respectively.

          Results

          We first demonstrated that TBI upregulated nine pro-inflammatory and/or neurodegenerative messenger RNAs (mRNAs) in the peripheral blood such as CXCL10, IL-18, IL-16, Cd-70, Mif, Ppbp, Ltd, Tnfrsf 11b, and Faslg. In addition to causing neurological injuries, TBI also upregulated the following 14 anti-inflammatory and/or neuroregenerative mRNAs in the peripheral blood such as Ccl19, Ccl3, Cxcl19, IL-10, IL-22, IL-6, Bmp6, Ccl22, IL-7, Bmp7, Ccl2, Ccl17, IL-1rn, and Gpi. Second, we observed that EP inhibited both neurological injuries and six pro-inflammatory and/or neurodegenerative genes (Cxcl10, IL-18, IL-16, Cd70, Mif, and Faslg) but potentiated four anti-inflammatory and/or neuroregenerative genes (Bmp6, IL-10, IL-22, and IL-6). Prior depletion of cerebral HSP70 with gene silence significantly reversed the beneficial effects of EP in reducing neurological injuries and altered gene profiles after a TBI. A positive Pearson correlation exists between IL-6 and HSP70 in the peripheral blood or in the cerebral levels. In addition, gene silence of cerebral HSP70 significantly reduced the overexpression of NF-κB, IL-6, and synapsin I in the ipsilateral brain regions after an EP in rats.

          Conclusions

          TBI causes neurological deficits associated with stimulating several pro-inflammatory gene profiles but inhibiting several anti-inflammatory gene profiles of cytokines and chemokines. Exercise protects against neurological injuries via stimulating an anti-inflammatory HSP70/NF-κB/IL-6/synapsin I axis in the injured brains.

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          Most cited references 71

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          Interleukin-6, a Major Cytokine in the Central Nervous System

          Interleukin-6 (IL-6) is a cytokine originally identified almost 30 years ago as a B-cell differentiation factor, capable of inducing the maturation of B cells into antibody-producing cells. As with many other cytokines, it was soon realized that IL-6 was not a factor only involved in the immune response, but with many critical roles in major physiological systems including the nervous system. IL-6 is now known to participate in neurogenesis (influencing both neurons and glial cells), and in the response of mature neurons and glial cells in normal conditions and following a wide arrange of injury models. In many respects, IL-6 behaves in a neurotrophin-like fashion, and seemingly makes understandable why the cytokine family that it belongs to is known as neuropoietins. Its expression is affected in several of the main brain diseases, and animal models strongly suggest that IL-6 could have a role in the observed neuropathology and that therefore it is a clear target of strategic therapies.
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            Interleukin-10 and related cytokines and receptors.

            The Class 2 alpha-helical cytokines consist of interleukin-10 (IL-10), IL-19, IL-20, IL-22, IL-24 (Mda-7), and IL-26, interferons (IFN-alpha, -beta, -epsilon, -kappa, -omega, -delta, -tau, and -gamma) and interferon-like molecules (limitin, IL-28A, IL-28B, and IL-29). The interaction of these cytokines with their specific receptor molecules initiates a broad and varied array of signals that induce cellular antiviral states, modulate inflammatory responses, inhibit or stimulate cell growth, produce or inhibit apoptosis, and affect many immune mechanisms. The information derived from crystal structures and molecular evolution has led to progress in the analysis of the molecular mechanisms initiating their biological activities. These cytokines have significant roles in a variety of pathophysiological processes as well as in regulation of the immune system. Further investigation of these critical intercellular signaling molecules will provide important information to enable these proteins to be used more extensively in therapy for a variety of diseases.
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              The Fas death factor.

               P Golstein,  S Nagata (1995)
              Fas ligand (FasL), a cell surface molecule belonging to the tumor necrosis factor family, binds to its receptor Fas, thus inducing apoptosis of Fas-bearing cells. Various cells express Fas, whereas FasL is expressed predominantly in activated T cells. In the immune system, Fas and FasL are involved in down-regulation of immune reactions as well as in T cell-mediated cytotoxicity. Malfunction of the Fas system causes lymphoproliferative disorders and accelerates autoimmune diseases, whereas its exacerbation may cause tissue destruction.
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                Author and article information

                Contributors
                chiocc@ms28.hinet.net
                790001@mail.chimei.org.tw
                cmh7590@mail.chimei.org.tw
                e612520@gmail.com
                891201@mail.chimei.org.tw
                u2001898@hotmail.com
                jessica@stust.edu.tw
                nych2525@gmail.com
                Journal
                J Neuroinflammation
                J Neuroinflammation
                Journal of Neuroinflammation
                BioMed Central (London )
                1742-2094
                24 April 2017
                24 April 2017
                2017
                : 14
                Affiliations
                [1 ]ISNI 0000 0004 0572 9255, GRID grid.413876.f, Department of Surgery, , Chi Mei Medical Center, ; Tainan, 710 Taiwan
                [2 ]ISNI 0000 0004 0572 9255, GRID grid.413876.f, Department of Emergency Medicine, , Chi Mei Medical Center, ; Tainan, 710 Taiwan
                [3 ]ISNI 0000 0004 0532 2914, GRID grid.412717.6, Department of Biotechnology, , Southern Taiwan University of Science and Technology, ; Tainan, 710 Taiwan
                [4 ]ISNI 0000 0004 0572 9255, GRID grid.413876.f, Division of General Surgery, Department of Surgery, , Chi Mei Medical Center, ; Tainan, 710 Taiwan
                [5 ]ISNI 0000 0004 0634 2255, GRID grid.411315.3, Department of Health and Nutrition, , Chia Nan University of Pharmacy and Science, ; Tainan, 717 Taiwan
                [6 ]ISNI 0000 0004 0572 9255, GRID grid.413876.f, Department of Medical Research, , Chi Mei Medical Center, ; Tainan, 710 Taiwan
                [7 ]Meridigen Biotech Co., Ltd, Taipei, 11493 Taiwan
                [8 ]ISNI 0000 0000 9337 0481, GRID grid.412896.0, The Ph.D. Program for Neural Regenerative Medicine, , Taipei Medical University, ; Taipei, 110 Taiwan
                Article
                867
                10.1186/s12974-017-0867-9
                5404305
                28438174
                6d7651a2-f5c6-470e-b9d9-2de0985e0495
                © The Author(s). 2017

                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.

                Funding
                Funded by: Ministry of Science and Technology (Taiwan)
                Award ID: NSC 102-2628-B-384-001-MY3
                Award Recipient :
                Funded by: Ministry of Science and Technology (Taiwan)
                Award ID: MOST 104-2314-B-384 -003 -MY3
                Award Recipient :
                Funded by: Ministry of Science and Technology (Taiwan)
                Award ID: MOST 104-2314-B-218 -001 -MY3
                Award Recipient :
                Funded by: Chi Mei Medical Center (Taiwan)
                Award ID: CMFHT 10504
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2017

                Neurosciences

                brain injury, neuroprotection, neuroinflammation, exercise, il-6, hsp70, synapsin i

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