PMID- 20673622 OWN - NLM STAT- MEDLINE DCOM- 20110315 LR - 20161125 IS - 1095-9157 (Electronic) IS - 0896-8411 (Linking) VI - 35 IP - 2 DP - 2010 Sep TI - Pro-inflammatory role of Anti-Ro/SSA autoantibodies through the activation of Furin-TACE-amphiregulin axis. PG - 160-70 LID - 10.1016/j.jaut.2010.06.020 [doi] AB - Prolonged inflammation can be detrimental because it may cause host toxicity and tissue damage. Indeed, excessive production of inflammatory cytokines is often associated with many autoimmune diseases. In this study we demonstrate that the anti-Ro/SSA autoantibodies (Abs) stimulate the production of pro-inflammatory cytokines IL-6 and IL-8 by human healthy salivary gland epithelial cells (healthy SGEC). The secretion of these cytokines is due to amphiregulin (AREG) that is overexpressed in healthy SGEC treated with anti-Ro/SSA Abs and in Sjogren's syndrome. We have discovered that the up-regulation of AREG occurs through TNF-alpha produced following anti-Ro/SSA Abs treatment. The gene silencing technique was used to study the AREG-TNF-alpha-IL-6/IL-8 secretion pathway, demonstrating that: (i) TNF-alpha gene silencing provokes a significant decrease of proinflammatory cytokines production and AREG expression in anti-Ro/SSA Abs-treated healthy SGEC; (ii) AREG gene silencing has a potent inhibitory effect on TNF-alpha-induced IL-6 and IL-8 secretion in healthy SGEC treated with anti-Ro/SSA Abs. These findings indicate that TACE-mediated AREG shedding plays a critical role in TNF-alpha-induced IL-6 and IL-8 secretion by the human healthy salivary gland epithelial cells, suggesting that this may be one of the possible intracellular mechanisms involved in the salivary glands inflammatory response in Sjogren's syndrome. CI - Copyright (c) 2010 Elsevier Ltd. All rights reserved. FAU - Lisi, Sabrina AU - Lisi S AD - Department of Human Anatomy and Histology, Laboratory of Cell Biology, University of Bari Medical School, piazza Giulio Cesare 1, Bari, Italy. s.lisi@anatomia.uniba.it FAU - Sisto, Margherita AU - Sisto M FAU - Lofrumento, Dario Domenico AU - Lofrumento DD FAU - Cucci, Liana AU - Cucci L FAU - Frassanito, Maria Antonia AU - Frassanito MA FAU - Mitolo, Vincenzo AU - Mitolo V FAU - D'Amore, Massimo AU - D'Amore M LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20100729 PL - England TA - J Autoimmun JT - Journal of autoimmunity JID - 8812164 RN - 0 (AREG protein, human) RN - 0 (Amphiregulin) RN - 0 (Autoantibodies) RN - 0 (EGF Family of Proteins) RN - 0 (Glycoproteins) RN - 0 (Intercellular Signaling Peptides and Proteins) RN - 0 (Interleukin-6) RN - 0 (Interleukin-8) RN - 0 (RNA, Small Interfering) RN - 0 (Ribonucleoproteins) RN - 0 (SS-A antigen) RN - 0 (Tumor Necrosis Factor-alpha) RN - EC 3.4.21.75 (Furin) RN - EC 3.4.24.- (ADAM Proteins) RN - EC 3.4.24.86 (ADAM17 Protein) RN - EC 3.4.24.86 (ADAM17 protein, human) SB - IM MH - ADAM Proteins/metabolism MH - ADAM17 Protein MH - Amphiregulin MH - Autoantibodies/*immunology/metabolism MH - Cells, Cultured MH - EGF Family of Proteins MH - Enzyme Activation/immunology MH - Epithelial Cells/immunology/*metabolism/pathology MH - Furin/genetics/metabolism MH - Gene Expression Regulation MH - Glycoproteins/genetics/metabolism MH - Humans MH - Intercellular Signaling Peptides and Proteins/genetics/metabolism MH - Interleukin-6/*biosynthesis/genetics MH - Interleukin-8/*biosynthesis/genetics MH - RNA, Small Interfering/genetics MH - Ribonucleoproteins/immunology MH - Salivary Glands/pathology MH - Signal Transduction MH - Sjogren's Syndrome/genetics/*immunology/metabolism MH - Tumor Necrosis Factor-alpha/genetics/metabolism EDAT- 2010/08/03 06:00 MHDA- 2011/03/16 06:00 CRDT- 2010/08/03 06:00 PHST- 2010/05/04 00:00 [received] PHST- 2010/06/29 00:00 [revised] PHST- 2010/06/30 00:00 [accepted] PHST- 2010/08/03 06:00 [entrez] PHST- 2010/08/03 06:00 [pubmed] PHST- 2011/03/16 06:00 [medline] AID - S0896-8411(10)00075-2 [pii] AID - 10.1016/j.jaut.2010.06.020 [doi] PST - ppublish SO - J Autoimmun. 2010 Sep;35(2):160-70. doi: 10.1016/j.jaut.2010.06.020. Epub 2010 Jul 29.