title: RETRACTED: Blockade of TNF-α signaling suppresses the AREG-mediated IL-6 and IL-8 cytokines secretion induced by anti-Ro/SSA autoantibodies.
abstract: The aim of this study was to analyze the Furin-TNF-α-converting enzyme (TACE)-amphiregulin (AREG)-IL-6/IL-8 secretion pathway in non-neoplastic human salivary gland epithelial cells (SGECs) stimulated with anti-Ro/SSA autoantibodies (Abs). We examined whether anti-Ro/SSA Abs-mediated TACE activation is responsible for AREG activation. As recent studies have demonstrated that AREG could induce proinflammatory cytokines secretion in epithelial cells, we discuss how TACE-mediated AREG shedding, caused by anti-Ro/SSA Abs treatment, could have a critical role in TNF-α-induced IL-6 and IL-8 secretion by SGEC. Furthermore, the effects of TNF-α blockade on AREG expression and TNF-α-AREG-mediated IL-6 and IL-8 secretion were evaluated. We have discovered that the upregulation of AREG occurs through TNF-α produced after anti-Ro/SSA Abs uptake via Fcγ receptors. Biological drug adalimumab and the gene silencing technique were used to study the AREG-IL-6/IL-8 secretion pathway, demonstrating that (i) adalimumab-mediated TNF-α blocking and TNF-α gene silencing provoke a significant decrease of proinflammatory cytokines production and AREG expression in anti-Ro/SSA Abs-treated SGEC; (ii) AREG gene silencing has a potent inhibitory effect on TNF-α-induced IL-6 and IL-8 secretion in SGEC treated with anti-Ro/SSA Abs; (iii) an inspection of the kinetics of cytokine production after exogeni TNF-α and AREG addition, and the use of cycloheximide in the presence of exogenous TNF-α as stimulant, clarified that TNF-α induces IL-6 and IL-8 secretion through AREG.Laboratory Investigation advance online publication, 20 September 2010; doi:10.1038/labinvest.2010.168.
authors.affiliation: Laboratory of Cell Biology, Department of Human Anatomy and Histology, University of Bari Medical School, Bari, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Sisto
authors.forename: Sabrina
authors.initials: S
authors.lastname: Lisi
authors.forename: Dario Domenico
authors.initials: DD
authors.lastname: Lofrumento
authors.forename: Liana
authors.initials: L
authors.lastname: Cucci
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Mitolo
authors.forename: Massimo
authors.initials: M
authors.lastname: D'Amore