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      Downregulation of proinflammatory cytokines in HTLV-1-infected T cells by Resveratrol

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          Abstract

          Background

          Human T-cell leukemia virus (HTLV-1) is a lymphotropic retrovirus associated to adult T cell leukemia (ATL) and to non-neoplastic inflammatory conditions affecting the central nervous system, lung or skin. The inflammatory disorders associated to HTLV-1 are mediated by different proinflammatory cytokines as IL-1α, IL-6, TNF-α. The release and the role of IL-17 is still debated. Aims of this study were to analyze IL-17 induction by HTLV-1 infection and to determine whether resveratrol (RES) is able to down regulate the pathway of cytokines production either in HTLV-1 chronically infected MT-2 cell line or in human CD4+ cells infected in vitro with HTLV-1.

          Methods

          MT-2 and HTLV-1 infected CD4+ cells were analyzed for proinflammatory cytokine production before or after RES treatment. The concentrations of IL-17, IL-1α, IL-6, and TNF-α were measured in cell culture supernatants by ELISA and SearchLight™ technology. The IL-17 mRNA expression was evaluated by RT-PCR. NF-kB activation was detected by non-radioactive, Electro Mobility Shift Assay (EMSA). HTLV-1 RNA expression was detected by Real-time-PCR (RQ-PCR).

          Results

          We found that RES is capable of inducing a dose-dependent inhibition of IL-1α, IL-6 and TNF-α production in vitro and can down regulate the expression of IL-17 at both mRNA and protein levels in HTLV-1 infected cells. This effect was associated with a dose-dependent inhibition of the of the nuclear factor kappa-B (NF-kB) activity. Conversely, RES did not apparently affect HTLV-1 proliferation.

          Conclusions

          These results support the anti-inflammatory properties of RES, suggesting that it might be a useful therapeutic agent for the treatment of HTLV-1 related inflammatory diseases.

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          Most cited references41

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          IL-17 stimulates the production and expression of proinflammatory cytokines, IL-beta and TNF-alpha, by human macrophages.

          IL-17 is a newly described, T cell-derived cytokine with ill-defined physiologic properties. As such, we examined the release of proinflammatory mediators by human macrophages in response to recombinant human (rh) IL-17. IL-1beta and TNF-alpha expression and synthesis were up-regulated by rhIL-17 in a dose (ED50 was 50 +/- 9 ng/ml)- and time-dependent fashion, with cytokine accumulation reaching a zenith after 9 h. Release of IL-6, PGE2, IL-10, IL-12, IL-1R antagonist, and stromelysin was also stimulated by rhIL-17. IL-1beta and TNF-alpha mRNA expression levels were controlled by rhIL-17 in a complex manner with an initial 30-min inhibitory phase, and then up-regulation beginning at 1 h and reaching a plateau at about 3 h. The latter expression pattern closely mirrored the nuclear accumulation of the transcription factor nuclear factor-kappaB. cAMP mimetics isobutyl-1-methylxanthine (IBMX), forskolin, PGE2, and cholera toxin reversed rhIL-17-induced release of TNF-alpha, but had no consistent effect on induced IL-1beta synthesis. Induced release of TNF-alpha was also inhibited by serine/threonine protein kinase inhibitors KT-5720 (protein kinase A) and Calphostin C (protein kinase C), mitogen-activated protein kinase kinase inhibitor PD098059, and a nonspecific tyrosine kinase inhibitor, genistein. Calphostin C alone abrogated the rhIL-17-induced release of IL-1beta. The antiinflammatory cytokines IL-4 (p < 0.01) and IL-10 (p < 0.02) completely reversed rhIL-17-stimulated IL-1beta release, while IL-13 and TGF-beta2 were partially effective (59 and 43% diminution, respectively). IL-10 exerted a significant suppressive effect on IL-17-induced TNF-alpha release (99%, p < 0.02), while the inhibitory effects of IL-4, IL-13, and TGF-beta2 on TNF-alpha secretion were partial (48, 10, and 23%, respectively). The data suggest a pivotal role for IL-17 in initiating and/or sustaining an inflammatory response.
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            IL-17 in Chronic Inflammation: From Discovery to Targeting.

            Interleukin-17 (IL-17) is a cytokine which elicits protection against extracellular bacterial and fungal infections and which plays important roles in inflammation. However, when produced in excess, it contributes to chronic inflammation associated with many inflammatory and autoimmune disorders. This has made IL-17 an attractive therapeutic target. The present review describes the structure of the IL-17 family, the IL-17 receptor complex, and the cells producing IL-17. The contributions of IL-17 to disease as well as new IL-17-based treatment options are discussed. Finally, the results of IL-17 or IL-17 receptor inhibitors in clinical trials are detailed. With a fruitful outlook, drug registration has now been granted for psoriasis psoriatic arthritis and ankylosing spondylitis, and also bears great potential in a growing number of conditions.
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              Clinical trials of resveratrol.

              An expanding body of preclinical evidence suggests resveratrol has the potential to impact a variety of human diseases. To translate encouraging experimental findings into human benefits, information is first needed on the safety, pharmacokinetics, pharmacodynamics, and, ultimately, clinical efficacy of resveratrol. Published clinical trials have largely focused on characterizing the pharmacokinetics and metabolism of resveratrol. Recent studies have also evaluated safety and potential mechanisms of activity following multiple dosing, and have found resveratrol to be safe and reasonably well-tolerated at doses of up to 5 g/day. However, the occurrence of mild to moderate side effects is likely to limit the doses employed in future trials to significantly less than this amount. This review describes the available clinical data, outlines how it supports the continuing development of resveratrol, and suggests what additional information is needed to increase the chances of success in future clinical trials. © 2011 New York Academy of Sciences.
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                Author and article information

                Contributors
                +39-64-9934610 , mariapia.fuggetta@ift.cnr.it
                valentina.bordignon@ifo.gov.it
                andrea.cottarelli@ift.cnr.it
                macchi@med.uniroma2.it
                catafrezza@hotmail.it
                paola.cordialifei@ifo.gov.it
                fabrizio.ensoli@ifo.gov.it
                stefania.ciafre@ift.cnr.it
                fmarino@unime.it
                antonio.mastino@unime.it
                Journal
                J Exp Clin Cancer Res
                J. Exp. Clin. Cancer Res
                Journal of Experimental & Clinical Cancer Research : CR
                BioMed Central (London )
                0392-9078
                1756-9966
                22 July 2016
                22 July 2016
                2016
                : 35
                : 118
                Affiliations
                [ ]Institute of Translational Pharmacology (IFT), National Research Council (CNR), Via Fosso del Cavaliere 100, 00133 Rome, Italy
                [ ]Laboratory of Clinical Pathology and Microbiology, San Gallicano Dermatologic Institute, Via Elio Chianesi, 53, 00144 Rome, Italy
                [ ]Department of System Medicine, University of Rome “Tor Vergata”, Via Montpellier 1, 00133 Rome, Italy
                [ ]Department of Biochemical Science and Surgery, University of Rome “Tor Vergata”, Via Montpellier 1, 00133 Rome, Italy
                [ ]Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences, University of Messina, 98166 Messina, Italy
                Article
                398
                10.1186/s13046-016-0398-8
                4957876
                27448598
                d09ba593-b1ab-4612-8619-10aa2da2c417
                © The Author(s). 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
                : 14 April 2016
                : 14 July 2016
                Categories
                Research
                Custom metadata
                © The Author(s) 2016

                Oncology & Radiotherapy
                resveratrol,htlv-1,inflammatory cytokines
                Oncology & Radiotherapy
                resveratrol, htlv-1, inflammatory cytokines

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