Effects of biological drug adalimumab on tumour necrosis factor-alpha-converting enzyme activation.
Tumour necrosis factor-alpha (TNF-alpha)-converting enzyme (TACE) is a membrane-bound metalloprotease and disintegrin. It is produced by a number of host cells and is known to shed and release cell-bound cytokines, particularly members of the TNF family. No investigations into the regulation of this enzyme by autoantibodies have been reported. In this study, we tested the hypothesis that anti-Ro/SSA autoantibodies, purified from IgG fractions of patients with primary Sjögren's syndrome, are capable to regulate TACE expression and activation in human salivary gland epithelial cells (SGEC). We also evaluated the potential physiological and therapeutic consequences of TNF-alpha blocking by the biological agent adalimumab, the first fully human (100% human peptide sequences) therapeutic anti-TNF-alpha antibody, on post-translational regulation of TACE. Taken together, our results show a dose-dependent increase in TACE expression in anti-Ro/SSA Abs-treated SGEC, followed by internalization, pro-domain shedding and activation of TACE protein. Adalimumab treatment brought TACE expression to levels than those observed in untreated SGEC. These findings, showing the presence of autoantibodies-dependent mechanisms by which TACE levels are regulated in human SGECs, may have implications in the context of current investigations on the pathological role of autoantibodies.
Lisi
Sabrina
S
Section of Cell Biology, Department of Human Anatomy and Histology, University of Bari Medical School, Bari, Italy. s.lisi@anatomia.uniba.it
Sisto
Margherita
M
D051722:ADAM Proteins / Q000096:biosynthesis* / Q000276:immunology; D000072198:ADAM17 Protein; D000068879:Adalimumab; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D001323:Autoantibodies / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D004848:Epithelium / Q000201:enzymology / Q000276:immunology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D012469:Salivary Glands / Q000201:enzymology* / Q000276:immunology; D012859:Sjogren's Syndrome / Q000188:drug therapy / Q000201:enzymology* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D001323:Autoantibodies; D014409:Tumor Necrosis Factor-alpha; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; D000068879:Adalimumab