Resolvin D1 prevents TNF-α-mediated disruption of salivary epithelial formation
Open Access
- 1 May 2012
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Cell Physiology
- Vol. 302 (9), C1331-C1345
- https://doi.org/10.1152/ajpcell.00207.2011
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.Keywords
This publication has 72 references indexed in Scilit:
- Inositol polyphosphate multikinase is a physiologic PI3-kinase that activates Akt/PKBProceedings of the National Academy of Sciences of the United States of America, 2011
- Rat Parotid Gland Cell Differentiation in Three-Dimensional CultureTissue Engineering, Part C: Methods, 2010
- Resolvin E1 Improves Tear Production and Decreases Inflammation in a Dry Eye Mouse ModelJournal of Ocular Pharmacology and Therapeutics, 2010
- Resolvins RvE1 and RvD1 attenuate inflammatory pain via central and peripheral actionsNature Medicine, 2010
- Resolvin D1 binds human phagocytes with evidence for proresolving receptorsProceedings of the National Academy of Sciences of the United States of America, 2010
- A complex interplay between Akt, TSC2 and the two mTOR complexesBiochemical Society Transactions, 2009
- Systems approach with inflammatory exudates uncovers novel anti-inflammatory and pro-resolving mediatorsProstaglandins, Leukotrienes & Essential Fatty Acids, 2008
- Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediatorsNature Reviews Immunology, 2008
- P2Y2 nucleotide receptor activation up-regulates vascular cell adhesion molecular-1 expression and enhances lymphocyte adherence to a human submandibular gland cell lineMolecular Immunology, 2008
- Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitiveNature, 2004