Sjogren's syndrome (SS) is an autoimmune disorder characterized by inflammation and dysfunction of salivary glands, resulting in impaired secretory function. The production of the pro-inflammatory cytokines tumor necrosis factor- (TNF) and interferon- (IFN) is elevated in exocrine glands of patients with SS, although little is known about the effects of these cytokines on salivary epithelial cell functions necessary for saliva secretion, including tight junction (TJ) integrity and the establishment of transepithelial ion gradients. The present study demonstrates that chronic exposure of polarized rat parotid gland (Par-C10) epithelial cell monolayers to TNF and IFN decreases transepithelial resistance (TER) and anion secretion, as measured by changes in short circuit current (I_sc) induced by carbachol, a muscarinic cholinergic receptor agonist, or UTP, a P2Y₂ nucleotide receptor agonist. In contrast, TNF and IFN had no effect on agonist-induced increases in the intracellular calcium concentration [Ca²⁺]_i in Par-C10 cells. Furthermore, treatment of Par-C10 cell monolayers with TNF and IFN increased paracellular permeability to normally impermeant proteins, altered cell and TJ morphology and downregulated the expression of the TJ protein, claudin-1, but not other TJ proteins expressed in Par-C10 cells. The decreases in TER, agonist-induced transepithelial anion secretion and claudin-1 expression caused by TNF, but not IFN, were reversible by incubation of Par-C10 monolayers with cytokine-free medium for 24 h, indicating that IFN causes irreversible inhibition of cellular activities associated with fluid secretion in salivary glands. Our results suggest that cytokine production is an important contributor to secretory dysfunction in SS by disrupting TJ integrity of salivary epithelium.