Τίτλος:
Transmembrane TNF-α reverse signaling inhibits lipopolysaccharide-induced proinflammatory cytokine formation in macrophages by inducing TGF-β: Therapeutic implications
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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.
Συγγραφείς:
Pallai, A.
Kiss, B.
Vereb, G.
Armaka, M.
Kollias, G.
Szekanecz, Z.
Szondy, Z.
Περιοδικό:
Journal of Immunological Methods
Εκδότης:
American Association of Immunologists
Λέξεις-κλειδιά:
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
DOI:
10.4049/jimmunol.1501573
