title: Resolvin D1 prevents TNF-α-mediated disruption of salivary epithelial formation.
abstract: Sjögren's syndrome is a chronic autoimmune disorder characterized by inflammation of salivary glands resulting in impaired secretory function. Our present studies indicate that chronic exposure of salivary epithelium to TNF-α and/or IFN-γ alters tight junction integrity, leading to secretory dysfunction. Resolvins of the D-series (RvDs) are endogenous lipid mediators derived from DHA that regulate excessive inflammatory responses leading to resolution and tissue homeostasis. In this study, we addressed the hypothesis that activation of the RvD1 receptor ALX/FPR2 in salivary epithelium prevents and/or resolves the TNF-α-mediated disruption of acinar organization and enhances monolayer formation. Our results indicate that 1) the RvD1 receptor ALX/FPR2 is present in fresh, isolated cells from mouse salivary glands and in cell lines of salivary origin; and 2) the agonist RvD1 (100 ng/ml) abolished tight junction and cytoskeletal disruption caused by TNF-α and enhanced cell migration and polarity in salivary epithelium. These effects were blocked by the ALX/FPR2 antagonist butyloxycarbonyl-Phe-Leu-Phe-Leu-Phe. The ALX/FPR2 receptor signals via modulation of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways since, in our study, blocking PI3K activation with LY294002, a potent and selective PI3K inhibitor, prevented RvD1-induced cell migration. Furthermore, Akt gene silencing with the corresponding siRNA almost completely blocked the ability of Par-C10 cells to migrate. Our findings suggest that RvD1 receptor activation promotes resolution of inflammation and tissue repair in salivary epithelium, which may have relevance in the restoration of salivary gland dysfunction associated with Sjögren's syndrome.
authors.affiliation: Department of Oral Biology, School of Dental Medicine, University at Buffalo, The State University of New York, Buffalo, New York 14214-3092, USA. .
authors.forename: Olutayo
authors.initials: O
authors.lastname: Odusanwo
authors.forename: Sreedevi
authors.initials: S
authors.lastname: Chinthamani
authors.forename: Andrew
authors.initials: A
authors.lastname: McCall
authors.forename: Michael E
authors.initials: ME
authors.lastname: Duffey
authors.forename: Olga J
authors.initials: OJ
authors.lastname: Baker
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002465:Cell Movement; D004281:Docosahexaenoic Acids / Q000378:metabolism* / Q000494:pharmacology; D004848:Epithelium / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D005260:Female; D055785:Gene Knockdown Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D034741:RNA, Small Interfering; D051381:Rats; D012469:Salivary Glands / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D012859:Sjogren's Syndrome / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C509871:HSH2 protein, mouse; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; C518399:resolvin D1; D004281:Docosahexaenoic Acids