title: TNF blocker drugs modulate human TNF-α-converting enzyme pro-domain shedding induced by autoantibodies.
abstract: Novel biologic therapies targeted against specific components of the immune system, including blockade of TNF-α have revolutionized therapeutic approaches to inflammatory conditions and systemic inhibitors of TNF-α have been approved for the treatment of a wide variety of autoimmune diseases. No studies aimed to elucidate the effects of anti-TNF-α blockers on tumour necrosis factor-α convertase (TACE) expression and activation have yet been published. TACE is the principal protease involved in the activation of pro-TNF-α and is a target for anti-TNF-α therapy. Here we focused on regulation of TACE expression in human salivary gland epithelial cells (SGEC) treated by anti-Ro/SSA autoantibodies (autoAbs), characterizing primary Sjögren's syndrome and on the effect of anti-Ro/SSA autoAbs on TACE pro-domain shedding and activation. To test the hypothesis that anti-TNF-α blocker drugs affect TACE expression, we used Adalimumab and Etanercept to block TNF-α and evaluate the effects of these biological agents on post-translational regulation of TACE. Anti-Ro/SSA autoAbs determines TACE pro-domain shedding suggesting that TACE activity is necessary for the release of TNF-α observed in anti-Ro/SSA autoAbs-stimulated cells. The comparative efficacy analysis of the regulation of TACE activity by Adalimumab and Etanercept revealed that Adalimumab appear to be significantly more efficacious than Etanercept in preventing TACE activation caused by anti-Ro/SSA autoAbs. It is intriguing to consider that regulation of TACE may participate in the pathogenic role of autoantibodies and the modulation of TACE expression by TNF-α antagonists might contribute to the beneficial effect of these drugs in inflammatory and autoimmune diseases.
authors.affiliation: Department of Human Anatomy and Histology, Section of Cell Biology, University of Bari Medical School, Bari, Italy. m.sisto@anatomia.uniba.it
authors.forename: Margherita
authors.initials: M
authors.lastname: Sisto
authors.forename: Sabrina
authors.initials: S
authors.lastname: Lisi
authors.forename: Dario D
authors.initials: DD
authors.lastname: Lofrumento
authors.forename: Simone
authors.initials: S
authors.lastname: Caprio
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Mitolo
authors.forename: Massimo
authors.initials: M
authors.lastname: D'Amore
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072198:ADAM17 Protein; D000068879:Adalimumab; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D001323:Autoantibodies / Q000494:pharmacology*; D001324:Autoantigens / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism; D000068800:Etanercept; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D011498:Protein Precursors / Q000737:chemistry / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D017434:Protein Structure, Tertiary / Q000502:physiology; D020733:RNA, Small Cytoplasmic / Q000276:immunology*; D018124:Receptors, Tumor Necrosis Factor; D012261:Ribonucleoproteins / Q000276:immunology*; D012469:Salivary Glands / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D012859:Sjogren's Syndrome / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000099207:SS-A Antigen
chemical_list: D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000068879:Adalimumab; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D001323:Autoantibodies; D001324:Autoantigens; D000068800:Etanercept; D007074:Immunoglobulin G; D011498:Protein Precursors; D020733:RNA, Small Cytoplasmic; D018124:Receptors, Tumor Necrosis Factor; D012261:Ribonucleoproteins; D014409:Tumor Necrosis Factor-alpha; C116006:RO60 protein, human; D000099207:SS-A Antigen; C061153:tumor necrosis factor precursor; C000606462:ADAM17 protein, human