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-a-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-a-induced IL-6 and IL-8 secretion by SGEC. Furthermore, the effects of TNF-a blockade on AREG expression and TNF-a-AREGmediated IL-6 and IL-8 secretion were evaluated. We have discovered that the upregulation of AREG occurs through TNF-a produced after anti-Ro/SSA Abs uptake via Fcg 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-a blocking and TNF-a 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-a-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-a and AREG addition, and the use of cycloheximide in the presence of exogenous TNF-a as stimulant, clarified that TNF-a induces IL-6 and IL-8 secretion through AREG.

Dexmedetomidine Modulates Histamine-induced Ca2+Signaling and Pro-inflammatory Cytokine Expression

“…Pro-inflammatory cytokine, most notably IL-6 is an important mediator of acute phase reaction and has been found in damaged areas of the salivary glands and have been implicated in the pathophysiology [ 36 37 ]. These results show that dexmedetomidine inhibited both histamine-evoked Ca 2+ mobilization ( Fig.…”

Occurrence of Salivary Gland Tumours in Two Patients Treated with Biological Agents

“…The malfunctioning of this enzyme contributes to pathogenic mechanisms of human diseases. TACE has been implicated in cancer, neurological and cardiovascular diseases, asthma and infections (6)(7)(8). In autoimmune diseases, upregulation of TACE was recently demonstrated in inflammatory synovial tissue from patients with RA, in PBMC of patients with multiple sclerosis and an altered TACE activity has been suggested in Crohn's disease mucosa (8)(9)(10).…”