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      Rhesus Macaque Theta Defensins Suppress Inflammatory Cytokines and Enhance Survival in Mouse Models of Bacteremic Sepsis


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          Theta-defensins (θ-defensins) are macrocyclic antimicrobial peptides expressed in leukocytes of Old World monkeys. The peptides are broad spectrum microbicides in vitro and numerous θ-defensin isoforms have been identified in granulocytes of rhesus macaques and Olive baboons. Several mammalian α- and β-defensins, genetically related to θ-defensins, have proinflammatory and immune-activating properties that bridge innate and acquired immunity. In the current study we analyzed the immunoregulatory properties of rhesus θ-defensins 1–5 (RTDs 1–5). RTD-1, the most abundant θ-defensin in macaques, reduced the levels of TNF, IL-1α, IL-1β, IL-6, and IL-8 secreted by blood leukocytes stimulated by several TLR agonists. RTDs 1–5 suppressed levels of soluble TNF released by bacteria- or LPS-stimulated blood leukocytes and THP-1 monocytes. Despite their highly conserved conformation and amino acid sequences, the anti-TNF activities of RTDs 1–5 varied by as much as 10-fold. Systemically administered RTD-1 was non-toxic for BALB/c mice, and escalating intravenous doses were well tolerated and non-immunogenic in adult chimpanzees. The peptide was highly stable in serum and plasma. Single dose administration of RTD-1 at 5 mg/kg significantly improved survival of BALB/c mice with E. coli peritonitis and cecal ligation-and-puncture induced polymicrobial sepsis. Peptide treatment reduced serum levels of several inflammatory cytokines/chemokines in bacteremic animals. Collectively, these results indicate that the anti-inflammatory properties of θ-defensins in vitro and in vivo are mediated by the suppression of numerous proinflammatory cytokines and blockade of TNF release may be a primary effect.

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          Defensins: antimicrobial peptides of innate immunity.

          Tomas Ganz (2003)
          The production of natural antibiotic peptides has emerged as an important mechanism of innate immunity in plants and animals. Defensins are diverse members of a large family of antimicrobial peptides, contributing to the antimicrobial action of granulocytes, mucosal host defence in the small intestine and epithelial host defence in the skin and elsewhere. This review, inspired by a spate of recent studies of defensins in human diseases and animal models, focuses on the biological function of defensins.
            • Record: found
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            • Article: not found

            TNF-mediated inflammatory disease.

            JR Bradley (2008)
            TNF was originally described as a circulating factor that can cause necrosis of tumours, but has since been identified as a key regulator of the inflammatory response. This review describes the known signalling pathways and cell biological effects of TNF, and our understanding of the role of TNF in human disease. TNF interacts with two different receptors, designated TNFR1 and TNFR2, which are differentially expressed on cells and tissues and initiate both distinct and overlapping signal transduction pathways. These diverse signalling cascades lead to a range of cellular responses, which include cell death, survival, differentiation, proliferation and migration. Vascular endothelial cells respond to TNF by undergoing a number of pro-inflammatory changes, which increase leukocyte adhesion, transendothelial migration and vascular leak and promote thrombosis. The central role of TNF in inflammation has been demonstrated by the ability of agents that block the action of TNF to treat a range of inflammatory conditions, including rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease and psoriasis. The increased incidence of infection in patients receiving anti-TNF treatment has highlighted the physiological role of TNF in infectious diseases. 2007 Pathological Society of Great Britain and Ireland
              • Record: found
              • Abstract: found
              • Article: not found

              Alarmins: chemotactic activators of immune responses.

              The recruitment and activation of antigen-presenting cells are critical early steps in mounting an immune response. Many microbial components and endogenous mediators participate in this process. Recent studies have identified a group of structurally diverse multifunctional host proteins that are rapidly released following pathogen challenge and/or cell death and, most importantly, are able to both recruit and activate antigen-presenting cells. These potent immunostimulants, including defensins, cathelicidin, eosinophil-derived neurotoxin, and high-mobility group box protein 1, serve as early warning signals to activate innate and adaptive immune systems. We propose to highlight these proteins' unique activities by grouping them under the novel term 'alarmins', in recognition of their role in mobilizing the immune system.

                Author and article information

                Role: Editor
                PLoS One
                PLoS ONE
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                6 December 2012
                : 7
                : 12
                : e51337
                [1 ]Department of Pathology and Laboratory Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
                [2 ]Kenneth Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, United States of America
                [3 ]Department of Pathology and Laboratory Medicine, University of California Irvine, Irvine, California, United States of America
                [4 ]Texas Biomedical Research Institute, San Antonio, Texas, United States of America
                Centre de Recherche Public de la Santé (CRP-Santé), Luxembourg
                Author notes

                Competing Interests: The authors have read the journal's policy and have the following conflicts: Michael E. Selsted is a member of Resolve Therapeutics, LLC, an entity that has optioned technology related to the therapeutic development of theta defensins for the treatment of systemic inflammation. A number of U.S. Patents have issued, all of which are assigned to the University of California (Antimicrobial Theta defensins U.S. 6,335,318 January 1, 2002, Antimicrobial theta defensins and methods of using same, U.S. 6,514,727 Feb. 4, 2003, U.S. 6,890,537 May 10, 2005, U.S. 7,399,823 B1 July 15, 2008, Antimicrobial theta defensins, analogs thereof, and methods of use, U.S. 7,119,070 October 10, 2006, U.S. 7,462,598 Dec. 9, 2008). This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.

                Conceived and designed the experiments: JS DT GO KR KB PT AO MS. Performed the experiments: JS DT GO KT KR KB PT. Analyzed the data: JS DT GO KR KB PT AO MS. Contributed reagents/materials/analysis tools: DT GO KR PT AO MS. Wrote the paper: JS DT PT AO MS.


                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.

                : 19 July 2012
                : 7 November 2012
                Page count
                Pages: 11
                This work was supported by National Institutes of Health grants to M. Selsted, (AI22931, AI58129 and DE021341), P. Tongaonkar (AI078321), A. Ouellette (DK044632 and AI059346) by the University of Southern California Norris Comprehensive Cancer Center Support Grant (P30 CA014089) from the National Cancer Institute, and SC CTSI (NIH/NCRR/NCATS) through Grant UL1RR031986. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No funds have been received from Resolve Therapeutics.
                Research Article
                Immune Defense
                Immunity to Infections
                Innate Immunity
                Immune Defense
                Innate Immunity
                Clinical Immunology
                Immune Activation
                Immune Defense
                Immunity to Infections
                Innate Immunity
                Immune Response
                Immune System



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