Dominant-negative inhibitors of soluble TNF attenuate experimental arthritis without suppressing innate immunity to infection
| Autor: | Paul Michael Steed, Araz Eivazi, James Kung, Stephen K. Doberstein, François Erard, Jonathan Zalevsky, Laure Janot, Sergei A. Ezhevsky, Bernhard Ryffel, Christopher D. O'Brien, David E. Szymkowski, Duc-Hanh T. Nguyen, Thomas Secher |
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| Přispěvatelé: | Xencor, Immunologie et Embryologie Moléculaires (IEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2007 |
| Předmět: |
Male
MESH: Arthritis Experimental medicine.medical_treatment Arthritis MESH: Recombinant Proteins Mice 0302 clinical medicine Immunology and Allergy Listeriosis MESH: Animals 0303 health sciences Mice Inbred BALB C U937 cell U937 Cells Caspase Inhibitors Recombinant Proteins 3. Good health Cytokine Mice Inbred DBA Caspases [SDV.IMM]Life Sciences [q-bio]/Immunology Tumor necrosis factor alpha Female MESH: Membrane Proteins medicine.symptom Inflammation Mediators MESH: Listeria Infections MESH: Cell Line Tumor Immunology MESH: Inflammation Mediators MESH: Mice Inbred BALB C Inflammation Biology MESH: U937 Cells 03 medical and health sciences Immune system Immunity Cell Line Tumor Paracrine Communication medicine Animals Humans MESH: Paracrine Communication MESH: Mice 030304 developmental biology MESH: Immunity Natural Innate immune system MESH: Caspases MESH: Humans MESH: Mice Inbred DBA Tumor Necrosis Factor-alpha Interleukin-8 Membrane Proteins medicine.disease Arthritis Experimental Immunity Innate MESH: Male MESH: Interleukin-8 MESH: Solubility Solubility MESH: Tumor Necrosis Factor-alpha MESH: Female 030217 neurology & neurosurgery |
| Zdroj: | Journal of Immunology Journal of Immunology, Publisher : Baltimore : Williams & Wilkins, c1950-. Latest Publisher : Bethesda, MD : American Association of Immunologists, 2007, 179 (3), pp.1872-83 Europe PubMed Central Scopus-Elsevier |
| ISSN: | 0022-1767 1550-6606 |
| Popis: | TNF is a pleiotropic cytokine required for normal development and function of the immune system; however, TNF overexpression also induces inflammation and is associated with autoimmune diseases. TNF exists as both a soluble and a transmembrane protein. Genetic studies in mice have suggested that inflammation in disease models involves soluble TNF (solTNF) and that maintenance of innate immune function involves transmembrane TNF (tmTNF). These findings imply that selective pharmacologic inhibition of solTNF may be anti-inflammatory and yet preserve innate immunity to infection. To address this hypothesis, we now describe dominant-negative inhibitors of TNF (DN-TNFs) as a new class of biologics that selectively inhibits solTNF. DN-TNFs blocked solTNF activity in human and mouse cells, a human blood cytokine release assay, and two mouse arthritis models. In contrast, DN-TNFs neither inhibited the activity of human or mouse tmTNF nor suppressed innate immunity to Listeria infection in mice. These results establish DN-TNFs as the first selective inhibitors of solTNF, demonstrate that inflammation in mouse arthritis models is primarily driven by solTNF, and suggest that the maintenance of tmTNF activity may improve the therapeutic index of future anti-inflammatory agents. |
| Databáze: | OpenAIRE |
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