title: The metalloproteinase ADAM17 and the epidermal growth factor receptor (EGFR) signaling drive the inflammatory epithelial response in Sjögren's syndrome.
abstract: Primary Sjögren's syndrome (pSS) is a chronic autoimmune disorder that particularly compromises the function of exocrine glands. The pathogenetic mechanisms of this autoimmune exocrinopathy have not been fully elucidated. Since increasing evidence actually suggests that the epidermal growth factor receptor (EGFR) pathway has a major impact on the inflammatory/immune reactions of the epithelial cells, in the apparent effort of enhancing innate immune defense while opposing overactivation of pro-inflammatory functions, the focus of the work presented here is clarify whether the EGFR-extracellular-signal-regulated kinase (ERK) pathway plays a role in the pro-inflammatory responses mounted by pSS salivary gland epithelial cells (SGEC). Investigations revealed that the EGFR-mediated activation of the downstream effectors ERK1/2 in pSS SGEC appeared to require ADAM17-dependent release of the endogenous EGFR ligand amphiregulin and transactivation of the EGFR. Moreover, blockade of amphiregulin bioactivity using a neutralizing Ab significantly reduced EGFR transactivation and ERK1/2 phosphorylation. In addition, pSS SGEC treated with the specific ADAM17 inhibitor TAPI-1 and with the EGFR inhibitor AG1478 exhibited deactivated AREG/EGFR/ERK signaling pathway and reduced pro-inflammatory cytokines released.
authors.affiliation: Laboratory of Cell Biology, Section of Human Anatomy and Histology, Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari Medical School, piazza Giulio Cesare 11, 70124, Bari, Italy, margherita.sisto@uniba.it.
authors.forename: Margherita
authors.initials: M
authors.lastname: Sisto
authors.forename: Sabrina
authors.initials: S
authors.lastname: Lisi
authors.forename: Massimo
authors.initials: M
authors.lastname: D'Amore
authors.forename: Dario Domenico
authors.initials: DD
authors.lastname: Lofrumento
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072198:ADAM17 Protein; D066258:Amphiregulin; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D066255:EGF Family of Proteins / Q000378:metabolism; D004847:Epithelial Cells / Q000502:physiology*; D066246:ErbB Receptors / Q000378:metabolism*; D006651:Histocytochemistry; D006801:Humans; D007150:Immunohistochemistry; D012469:Salivary Glands / Q000473:pathology*; D015398:Signal Transduction; D012859:Sjogren's Syndrome / Q000473:pathology*
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; D016207:Cytokines; D066255:EGF Family of Proteins; D066246:ErbB Receptors; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human