@article{3001529,
    title = "Transmembrane TNF-α reverse signaling inhibits lipopolysaccharide-induced proinflammatory cytokine formation in macrophages by inducing TGF-β: Therapeutic implications",
    author = "Pallai, A. and Kiss, B. and Vereb, G. and Armaka, M. and Kollias, G. and Szekanecz, Z. and Szondy, Z.",
    journal = "Journal of Immunological Methods",
    year = "2016",
    volume = "196",
    number = "3",
    pages = "1146-1157",
    publisher = "American Association of Immunologists",
    issn = "0022-1759",
    doi = "10.4049/jimmunol.1501573",
    keywords = "mitogen activated protein kinase;  mitogen activated protein kinase kinase 3;  mitogen activated protein kinase kinase 6;  mitogen activated protein kinase p38;  phosphatidylinositol 3 kinase;  transforming growth factor beta;  tumor necrosis factor alpha;  antiinflammatory agent;  cytokine;  lipopolysaccharide;  transforming growth factor beta;  tumor necrosis factor alpha, animal cell;  animal experiment;  Article;  cell surface;  controlled study;  cytokine production;  down regulation;  enzyme activation;  enzyme activity;  macrophage;  male;  mouse;  nonhuman;  priority journal;  protein expression;  protein function;  protein targeting;  signal transduction;  upregulation;  animal;  apoptosis;  biosynthesis;  confocal microscopy;  drug effects;  fluorescent antibody technique;  human;  immunohistochemistry;  immunology;  polymerase chain reaction;  signal transduction;  Western blotting, Animals;  Anti-Inflammatory Agents;  Apoptosis;  Blotting, Western;  Cytokines;  Fluorescent Antibody Technique;  Humans;  Immunohistochemistry;  Lipopolysaccharides;  Macrophages;  Male;  Mice;  Microscopy, Confocal;  Polymerase Chain Reaction;  Signal Transduction;  Transforming Growth Factor beta;  Tumor Necrosis Factor-alpha",
    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 immunesuppressive effect of mTNF-α is mediated via TGF-β. Although apoptotic cells are also known to suppress LPS-induced proin-flammatory 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. © 2016 by The American Association of Immunologists, Inc."
}