Proinflammatory cytokines tumor necrosis factor-α and interferon-γ alter tight junction structure and function in the rat parotid gland Par-C10 cell line

Olga J. Baker, Jean M. Camden, Robert S. Redman, Jonathan E. Jones, Cheikh Seye, Laurie Erb, Gary A. Weisman

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

Sjögren's syndrome (SS) is an autoimmune disorder characterized by inflammation and dysfunction of salivary glands, resulting in impaired secretory function. The production of the proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) 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-α and IFN-γ decreases transepithelial resistance (TER) and anion secretion, as measured by changes in short-circuit current (Isc) induced by carbachol, a muscarinic cholinergic receptor agonist, or UTP, a P2Y2 nucleotide receptor agonist. In contrast, TNF- and IFN-γ 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-α and IFN-γ 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-α, but not IFN-β, were reversible by incubation of Par-C10 cell monolayers with cytokine-free medium for 24 h, indicating that IFN-γ 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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Cell Physiology
Volume295
Issue number5
DOIs
StatePublished - Nov 2008
Externally publishedYes

Fingerprint

Tight Junctions
Parotid Gland
Interferons
Tumor Necrosis Factor-alpha
Cytokines
Cell Line
Claudin-1
Anions
Purinergic P2Y2 Receptors
Epithelial Cells
Zonula Occludens-1 Protein
Exocrine Glands
Sialadenitis
Tight Junction Proteins
Fluids and Secretions
Muscarinic Agonists
Uridine Triphosphate
Intercellular Junctions
Carbachol
Cholinergic Receptors

Keywords

  • Claudin-1
  • Ion secretion
  • Salivary epithelium
  • Sjögren's syndrome

ASJC Scopus subject areas

  • Cell Biology
  • Physiology

Cite this

Proinflammatory cytokines tumor necrosis factor-α and interferon-γ alter tight junction structure and function in the rat parotid gland Par-C10 cell line. / Baker, Olga J.; Camden, Jean M.; Redman, Robert S.; Jones, Jonathan E.; Seye, Cheikh; Erb, Laurie; Weisman, Gary A.

In: American Journal of Physiology - Cell Physiology, Vol. 295, No. 5, 11.2008.

Research output: Contribution to journalArticle

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abstract = "Sj{\"o}gren's syndrome (SS) is an autoimmune disorder characterized by inflammation and dysfunction of salivary glands, resulting in impaired secretory function. The production of the proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) 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-α and IFN-γ decreases transepithelial resistance (TER) and anion secretion, as measured by changes in short-circuit current (Isc) induced by carbachol, a muscarinic cholinergic receptor agonist, or UTP, a P2Y2 nucleotide receptor agonist. In contrast, TNF- and IFN-γ 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-α and IFN-γ 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-α, but not IFN-β, were reversible by incubation of Par-C10 cell monolayers with cytokine-free medium for 24 h, indicating that IFN-γ 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.",
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AU - Baker, Olga J.

AU - Camden, Jean M.

AU - Redman, Robert S.

AU - Jones, Jonathan E.

AU - Seye, Cheikh

AU - Erb, Laurie

AU - Weisman, Gary A.

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AB - Sjögren's syndrome (SS) is an autoimmune disorder characterized by inflammation and dysfunction of salivary glands, resulting in impaired secretory function. The production of the proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) 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-α and IFN-γ decreases transepithelial resistance (TER) and anion secretion, as measured by changes in short-circuit current (Isc) induced by carbachol, a muscarinic cholinergic receptor agonist, or UTP, a P2Y2 nucleotide receptor agonist. In contrast, TNF- and IFN-γ 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-α and IFN-γ 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-α, but not IFN-β, were reversible by incubation of Par-C10 cell monolayers with cytokine-free medium for 24 h, indicating that IFN-γ 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.

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