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 ResearchResearch AreasSaliva and Salivary GlandsBaker     July 1, 2015  

Saliva and Salivary Glands

Olga Baker, DDS, PhD personal profile

Regulation of salivary gland secretion

Sjögren’s Syndrome (SS) is a chronic, autoimmune disorder characterized by inflammation and dysfunction of salivary and lacrimal glands, resulting in impaired secretory function. The pathophysiology of SS has been associated with elevated levels of pro-inflammatory cytokines, such as tumor necrosis factor-α (TNFα), interferon-γ (IFNγ), IL-1β, interleukin-6 (IL-6), interleukin-18 (IL-18) and interleukin-12 (IL-12). SS-associated cytokines are elevated in both plasma and minor salivary glands of patients with Sjögren’s syndrome (SS) and in plasma and major salivary glands of animal models of SS. In salivary glands tight junction proteins (TJs) are necessary to establish transepithelial gradients that drive saliva secretion. Cytokines have been shown to alter intestinal and airway epithelial cell tight junction (TJ) structure and function. Alteration of the integrity of intercellular TJs of intestinal or airway epithelium has been associated with Crohn’s disease, celiac sprue and cystic fibrosis. However, little is known about the effects of SS-associated cytokines on epithelial cell TJs in salivary epithelial dysfunction.

Our studies demonstrate that chronic exposure of polarized rat parotid gland (Par-C10) epithelial cell monolayers to TNFα and/or IFNγ decreases transepithelial resistance (TER) and transepithelial anion secretion induced by carbachol, a muscarinic cholinergic receptor agonist. Our studies show that among the TJ proteins, claudin-1 is selectively downregulated by TNFα and/or IFNγ treatment of Par-C10 cells. In cells treated with TNFα, claudin-1 expression returns to pre-treatment levels within a 24 h incubation with cytokine-free medium. Under these conditions, recovery of claudin-1 expression corresponds with increases in TER and agonist-induced short circuit current (Isc). We have obtained new data demonstrating that silencing of claudin-1 expression decreases TER in Par-C10 monolayers. Furthermore, the cellular distribution of the TJ proteins occludin and ZO-1 is altered by TNFα and/or IFNγ treatment in Par-C10 three-dimensional (3D) acinar spheres. Based on these findings, ongoing projects in the Baker lab are to:

  • Understand how TJ are modulated during saliva secretion.

  • Examine the cytokine-induced changes in the expression and/or distribution of TJ proteins in salivary glands, consistent with a loss in saliva secretion.

  • Identify the molecular mechanisms underlying cytokine-induced disruption of TJ integrity using in vitro and in vivo models of SS.

 Our studies will provide a greater understanding the mechanisms whereby saliva secretion is decreased during the pro-inflammatory stages of salivary gland diseases, a significant initial step in defining signaling pathways that regulate TJ structural integrity in salivary acini.