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      MTADV 5-MER peptide suppresses chronic inflammations as well as autoimmune pathologies and unveils a new potential target-Serum Amyloid A.

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          Abstract

          Despite the existence of potent anti-inflammatory biological drugs e.g., anti-TNF and anti IL-6 receptor antibodies, for treating chronic inflammatory and autoimmune diseases, these are costly and not specific. Cheaper oral available drugs remain an unmet need. Expression of the acute phase protein Serum Amyloid A (SAA) is dependent on release of pro-inflammatory cytokines IL-1, IL-6 and TNF-α during inflammation. Conversely, SAA induces pro-inflammatory cytokine secretion, including Th17, leading to a pathogenic vicious cycle and chronic inflammation. 5- MER peptide (5-MP) MTADV (methionine-threonine-alanine-aspartic acid-valine), also called Amilo-5MER, was originally derived from a sequence of a pro-inflammatory CD44 variant isolated from synovial fluid of a Rheumatoid Arthritis (RA) patient. This human peptide displays an efficient anti-inflammatory effects to ameliorate pathology and clinical symptoms in mouse models of RA, Inflammatory Bowel Disease (IBD) and Multiple Sclerosis (MS). Bioinformatics and qRT-PCR revealed that 5-MP, administrated to encephalomyelytic mice, up-regulates genes contributing to chronic inflammation resistance. Mass spectrometry of proteins that were pulled down from an RA synovial cell extract with biotinylated 5-MP, showed that it binds SAA. 5-MP disrupted SAA assembly, which is correlated with its pro-inflammatory activity. The peptide MTADV (but not scrambled TMVAD) significantly inhibited the release of pro-inflammatory cytokines IL-6 and IL-1β from SAA-activated human fibroblasts, THP-1 monocytes and peripheral blood mononuclear cells. 5-MP suppresses the pro-inflammatory IL-6 release from SAA-activated cells, but not from non-activated cells. 5-MP could not display therapeutic activity in rats, which are SAA deficient, but does inhibit inflammations in animal models of IBD and MS, both are SAA-dependent, as shown by others in SAA knockout mice. In conclusion, 5-MP suppresses chronic inflammation in animal models of RA, IBD and MS, which are SAA-dependent, but not in animal models, which are SAA-independent.

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          Author and article information

          Journal
          J Autoimmun
          Journal of autoimmunity
          Elsevier BV
          1095-9157
          0896-8411
          November 2021
          : 124
          Affiliations
          [1 ] The Lautenberg Center of Immunology and Cancer Research, Faculty of Medicine, Hebrew University of Jerusalem, Israel.
          [2 ] Department of Biomedical Engineering, Tandon School of Engineering, New York University, New York, NY, USA.
          [3 ] Othmer-Jacobs Department of Chemical and Biomolecular Engineering, Tandon School of Engineering, Brooklyn, USA.
          [4 ] Department of Neurology, Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
          [5 ] Spherium Biomed, Barcelona, Spain.
          [6 ] Orthopedic Surgery Department, Hadassah University Hospital, Jerusalem, Israel.
          [7 ] Department of Pathology, Hadassah University Hospital, Jerusalem, Israel.
          [8 ] Biotechnologies and Biopharmaceutics, University of Bari, Bari, 70126, Italy.
          [9 ] Bioinformatics Unit of the Hebrew University of Jerusalem and Hadassah Medical Center, Israel.
          [10 ] Lung Cellular and Molecular Biology Laboratory, Institute of Pulmonary Medicine, Hadassah-Hebrew University Medical Center, Israel.
          [11 ] The Lautenberg Center of Immunology and Cancer Research, Faculty of Medicine, Hebrew University of Jerusalem, Israel. Electronic address: davidn@ekmd.huji.ac.il.
          Article
          S0896-8411(21)00121-9
          10.1016/j.jaut.2021.102713
          34390919
          4ff97e00-c020-484e-9e8c-c0bc3f1236ca
          History

          Cytokines,Inflammation,Peptide,Serum amyloid A,Therapy
          Cytokines, Inflammation, Peptide, Serum amyloid A, Therapy

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