title: Transmembrane TNF-α Reverse Signaling Inhibits Lipopolysaccharide-Induced Proinflammatory Cytokine Formation in Macrophages by Inducing TGF-β: Therapeutic Implications.
abstract: TNF-α, a potent proinflammatory cytokine, is generated in a precursor form called transmembrane (m)TNF-α that is expressed as a type II polypeptide on the surface of certain cells. mTNF-α was shown to act both as a ligand by binding to TNF-α receptors, as well as a receptor that transmits outside-to-inside (reverse) signals back into the mTNF-α-bearing cells. In this study, we show that nonactivated macrophages express basal levels of mTNF-α and respond to anti-TNF-α Abs by triggering the MAPK kinase 4 signaling pathway. The pathway induces TGF-β. Based on inhibitory experiments, the production of TGF-β1 is regulated via Jun kinases, whereas that of other TGF-βs is regulated via p38 MAPKs. Exposure to LPS further induced the expression of mTNF-α, and triggering of mTNF-α strongly suppressed the LPS-induced proinflammatory response. Neutralizing TGF-β by Abs prevented the mTNF-α-mediated suppression of LPS-induced proinflammatory cytokine formation, indicating that the immune-suppressive effect of mTNF-α is mediated via TGF-β. Although apoptotic cells are also known to suppress LPS-induced proinflammatory cytokine formation in macrophages by upregulating TGF-β, we show that they do not use the mTNF-α signaling pathway. Because TGF-β possesses a wide range of immune-suppressive effects, our data indicate that upregulation of TGF-β synthesis by those TNF-α-targeting molecules, which are able to trigger mTNF-α, might contribute to their therapeutic effect in the treatment of certain inflammatory diseases such as Crohn's disease, Wegener's granulomatosis, or sarcoidosis. Additionally, none of the TNF-α-targeting molecules is expected to interfere with the immune-silencing effects of apoptotic cells.
authors.affiliation: Division of Dental Biochemistry, Department of Biochemistry and Molecular Biology, University of Debrecen, H-4012 Debrecen, Hungary;
authors.forename: Anna
authors.initials: A
authors.lastname: Pallai
authors.affiliation: Division of Dental Biochemistry, Department of Biochemistry and Molecular Biology, University of Debrecen, H-4012 Debrecen, Hungary;
authors.forename: Beáta
authors.initials: B
authors.lastname: Kiss
authors.affiliation: Department of Biophysics and Cell Biology, Research Center of Molecular Medicine, University of Debrecen, H-4012 Debrecen, Hungary;
authors.forename: György
authors.initials: G
authors.lastname: Vereb
authors.affiliation: Division of Immunology, Biomedical Sciences Research Center Alexander Fleming, 16672 Vari, Greece;
authors.forename: Marietta
authors.identifier: http://orcid.org/0000-0003-0985-9076
authors.initials: M
authors.lastname: Armaka
authors.affiliation: Division of Immunology, Biomedical Sciences Research Center Alexander Fleming, 16672 Vari, Greece; Department of Physiology, School of Medicine, National and Kapodistrian University of Athens, 15771 Athens, Greece; and.
authors.forename: George
authors.initials: G
authors.lastname: Kollias
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, University of Debrecen, H-4012 Debrecen, Hungary.
authors.forename: Zoltán
authors.identifier: http://orcid.org/0000-0002-7794-6844
authors.initials: Z
authors.lastname: Szekanecz
authors.affiliation: Division of Dental Biochemistry, Department of Biochemistry and Molecular Biology, University of Debrecen, H-4012 Debrecen, Hungary; szondy@med.unideb.hu.
authors.forename: Zsuzsa
authors.initials: Z
authors.lastname: Szondy
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D017209:Apoptosis / Q000276:immunology; D015153:Blotting, Western; D016207:Cytokines / Q000096:biosynthesis* / Q000276:immunology; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D008297:Male; D051379:Mice; D018613:Microscopy, Confocal; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D008070:Lipopolysaccharides; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha