Pro-inflammatory role of Anti-Ro/SSA autoantibodies through the activation of Furin-TACE-amphiregulin axis.
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 Sjögren'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 Sjögren's syndrome.
Lisi
Sabrina
S
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
Sisto
Margherita
M
Lofrumento
Dario Domenico
DD
Cucci
Liana
L
Frassanito
Maria Antonia
MA
Mitolo
Vincenzo
V
D'Amore
Massimo
M
D051722:ADAM Proteins / Q000378:metabolism; D000072198:ADAM17 Protein; D066258:Amphiregulin; D001323:Autoantibodies / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D066255:EGF Family of Proteins; D004789:Enzyme Activation / Q000276:immunology; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D045683:Furin / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D012261:Ribonucleoproteins / Q000276:immunology; D012469:Salivary Glands / Q000473:pathology; D015398:Signal Transduction; D012859:Sjogren's Syndrome / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D000099207:SS-A Antigen
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D066258:Amphiregulin; D001323:Autoantibodies; D066255:EGF Family of Proteins; D045683:Furin; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; D016209:Interleukin-8; D034741:RNA, Small Interfering; D012261:Ribonucleoproteins; D014409:Tumor Necrosis Factor-alpha; D000099207:SS-A Antigen; C587848:AREG protein, human; C000606462:ADAM17 protein, human