title: Transmembrane TNF-alpha reverse signaling leading to TGF-beta production is selectively activated by TNF targeting molecules: Therapeutic implications.
abstract: Tumor necrosis factor (TNF)-α is a potent pro-inflammatory cytokine exerting pleiotropic effects on various cell types. It is synthesized in a precursor form called transmembrane TNF-α (mTNF-α) which, after being processed by metalloproteinases, is released in a soluble form to mediate its biological activities through Type 1 and 2 TNF receptors in TNF receptor expressing cells. In addition to acting in soluble form, TNF-α also acts in the transmembrane form both as a ligand by activating TNF receptors, as well as a receptor that transmits outside-to-inside (reverse) signals back into mTNF-α bearing cells. Since the discovery that TNF-α plays a determining role in the pathogenesis of several chronic inflammatory diseases, anti-TNF agents are increasingly being used in the treatment of a rapidly expanding number of rheumatic and systemic autoimmune diseases, such as rheumatoid arthritis, Crohn's disease, psoriasis, psoriatic arthritis, ankyloting spondylitis, Wegener granulomatosis and sarcoidosis. There are 5 TNF antagonists currently available: etanercept, a soluble TNF receptor construct; infliximab, a chimeric monoclonal antibody; adalimumab and golimumab, fully human antibodies; and certolizumab pegol, an Fab' fragment of a humanized anti-TNF-α antibody. Though each compound can efficiently neutralize TNF-α, increasing evidence suggests that they show different efficacy in the treatment of these diseases. These observations indicate that in addition to neutralizing TNF-α, other biological effects induced by TNF-α targeting molecules dictate the success of the therapy. Recently, we found that mTNF-α reverse signaling leads to transforming growth factor (TGF)-β production in macrophages and anti-TNF agents selectively trigger this pathway. In this review we will focus on the potential contribution of the activation of the mTNF-α signaling pathway to the success of the anti-TNF therapy.
authors.affiliation: Dental Biochemistry Section of Department of Basic Medical Science, Research Center of Molecular Medicine, University of Debrecen, Nagyerdei krt. 98. Debrecen, Hungary; Department of Biochemistry and Molecular Biology, Research Center of Molecular Medicine, University of Debrecen, Nagyerdei krt. 98. Debrecen, Hungary. Electronic address: szondy@med.unideb.hu.
authors.forename: Zsuzsa
authors.initials: Z
authors.lastname: Szondy
authors.affiliation: Dental Biochemistry Section of Department of Basic Medical Science, Research Center of Molecular Medicine, University of Debrecen, Nagyerdei krt. 98. Debrecen, Hungary; Department of Biochemistry and Molecular Biology, Research Center of Molecular Medicine, University of Debrecen, Nagyerdei krt. 98. Debrecen, Hungary.
authors.forename: Anna
authors.initials: A
authors.lastname: Pallai
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D008565:Membrane Proteins; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha
keywords: Effectiveness; TGF-β; TNF targeting molecules; mTNF-α