Proinflammatory cytokines tumor necrosis factor-alpha and interferon-gamma alter tight junction structure and function in the rat parotid gland Par-C10 cell line
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-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) is elevated in e...
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description | 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-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) 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-alpha and IFN-gamma 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 P2Y(2) nucleotide receptor agonist. In contrast, TNF-alpha and IFN-gamma had no effect on agonist-induced increases in the intracellular calcium concentration [Ca(2+)](i) in Par-C10 cells. Furthermore, treatment of Par-C10 cell monolayers with TNF-alpha and IFN-gamma 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-alpha, but not IFN-gamma, were reversible by incubation of Par-C10 cell monolayers with cytokine-free medium for 24 h, indicating that IFN-gamma 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. |
doi_str_mv | 10.1152/ajpcell.00144.2008 |
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The production of the proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) 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-alpha and IFN-gamma 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 P2Y(2) nucleotide receptor agonist. In contrast, TNF-alpha and IFN-gamma had no effect on agonist-induced increases in the intracellular calcium concentration [Ca(2+)](i) in Par-C10 cells. Furthermore, treatment of Par-C10 cell monolayers with TNF-alpha and IFN-gamma 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-alpha, but not IFN-gamma, were reversible by incubation of Par-C10 cell monolayers with cytokine-free medium for 24 h, indicating that IFN-gamma 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.</description><identifier>ISSN: 0363-6143</identifier><identifier>EISSN: 1522-1563</identifier><identifier>DOI: 10.1152/ajpcell.00144.2008</identifier><identifier>PMID: 18768927</identifier><language>eng</language><publisher>United States: American Physiological Society</publisher><subject>Animals ; Calcium - metabolism ; Carbachol - pharmacology ; Cell Line, Transformed ; Cell Shape ; Claudin-1 ; Electric Impedance ; Inflammation Mediators - metabolism ; Interferon-gamma - metabolism ; Membrane Proteins - metabolism ; Muscarinic Agonists - pharmacology ; Parotid Gland - cytology ; Parotid Gland - drug effects ; Parotid Gland - immunology ; Parotid Gland - ultrastructure ; Permeability ; Rats ; Receptors and Signal Transduction ; Receptors, Purinergic P2 - metabolism ; Receptors, Purinergic P2Y2 ; Saliva - metabolism ; Tight Junctions - drug effects ; Tight Junctions - immunology ; Tight Junctions - ultrastructure ; Time Factors ; Tumor Necrosis Factor-alpha - metabolism ; Uridine Triphosphate - metabolism</subject><ispartof>American Journal of Physiology: Cell Physiology, 2008-11, Vol.295 (5), p.C1191-C1201</ispartof><rights>Copyright © 2008, American Physiological Society 2008</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c400t-547bda980ac62797641e37c2af039d0e46990da4dedad01391f953447d15822b3</citedby><cites>FETCH-LOGICAL-c400t-547bda980ac62797641e37c2af039d0e46990da4dedad01391f953447d15822b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,3026,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18768927$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Baker, Olga J</creatorcontrib><creatorcontrib>Camden, Jean M</creatorcontrib><creatorcontrib>Redman, Robert S</creatorcontrib><creatorcontrib>Jones, Jonathan E</creatorcontrib><creatorcontrib>Seye, Cheikh I</creatorcontrib><creatorcontrib>Erb, Laurie</creatorcontrib><creatorcontrib>Weisman, Gary A</creatorcontrib><title>Proinflammatory cytokines tumor necrosis factor-alpha and interferon-gamma alter tight junction structure and function in the rat parotid gland Par-C10 cell line</title><title>American Journal of Physiology: Cell Physiology</title><addtitle>Am J Physiol Cell Physiol</addtitle><description>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-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) 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-alpha and IFN-gamma 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 P2Y(2) nucleotide receptor agonist. In contrast, TNF-alpha and IFN-gamma had no effect on agonist-induced increases in the intracellular calcium concentration [Ca(2+)](i) in Par-C10 cells. Furthermore, treatment of Par-C10 cell monolayers with TNF-alpha and IFN-gamma 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-alpha, but not IFN-gamma, were reversible by incubation of Par-C10 cell monolayers with cytokine-free medium for 24 h, indicating that IFN-gamma 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.</description><subject>Animals</subject><subject>Calcium - metabolism</subject><subject>Carbachol - pharmacology</subject><subject>Cell Line, Transformed</subject><subject>Cell Shape</subject><subject>Claudin-1</subject><subject>Electric Impedance</subject><subject>Inflammation Mediators - metabolism</subject><subject>Interferon-gamma - metabolism</subject><subject>Membrane Proteins - metabolism</subject><subject>Muscarinic Agonists - pharmacology</subject><subject>Parotid Gland - cytology</subject><subject>Parotid Gland - drug effects</subject><subject>Parotid Gland - immunology</subject><subject>Parotid Gland - ultrastructure</subject><subject>Permeability</subject><subject>Rats</subject><subject>Receptors and Signal Transduction</subject><subject>Receptors, Purinergic P2 - metabolism</subject><subject>Receptors, Purinergic P2Y2</subject><subject>Saliva - metabolism</subject><subject>Tight Junctions - drug effects</subject><subject>Tight Junctions - immunology</subject><subject>Tight Junctions - ultrastructure</subject><subject>Time Factors</subject><subject>Tumor Necrosis Factor-alpha - metabolism</subject><subject>Uridine Triphosphate - metabolism</subject><issn>0363-6143</issn><issn>1522-1563</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkcuO1DAQRS0EYpqBH2CBvGKXxq848QYJtXhJIzELWFvVttPtxrGD7YzUn8Ofksw0r5Wlqnuvq-og9JKSLaUtewOnybgQtoRQIbaMkP4R2iwN1tBW8sdoQ7jkjaSCX6FnpZwIIYJJ9RRd0b6TvWLdBv28zcnHIcA4Qk35jM25pu8-uoLrPKaMozM5FV_wAGYRNBCmI2CIFvtYXR5cTrE5rHYMYSng6g_Hik9zNNWniEvNs6lzdvee4XfZR1yPDmeoeIKcqrf4EFbFLeRmRwleN8NhGeQ5ejJAKO7F5b1G3z68_7r71Nx8-fh59-6mMYKQ2rSi21tQPQEjWac6KajjnWEwEK4scUIqRSwI6yxYQrmig2q5EJ2lbc_Ynl-jtw-507wfnTUu1gxBT9mPkM86gdf_d6I_6kO606ztherVEvD6EpDTj9mVqkdf1jUgujQXLVXXS0n6RcgehOtlS3bDn08o0StZfSGr78nqlexievXveH8tF5T8F_3gpe4</recordid><startdate>20081101</startdate><enddate>20081101</enddate><creator>Baker, Olga J</creator><creator>Camden, Jean M</creator><creator>Redman, Robert S</creator><creator>Jones, Jonathan E</creator><creator>Seye, Cheikh I</creator><creator>Erb, Laurie</creator><creator>Weisman, Gary A</creator><general>American Physiological Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20081101</creationdate><title>Proinflammatory cytokines tumor necrosis factor-alpha and interferon-gamma alter tight junction structure and function in the rat parotid gland Par-C10 cell line</title><author>Baker, Olga J ; Camden, Jean M ; Redman, Robert S ; Jones, Jonathan E ; Seye, Cheikh I ; Erb, Laurie ; Weisman, Gary A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c400t-547bda980ac62797641e37c2af039d0e46990da4dedad01391f953447d15822b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Animals</topic><topic>Calcium - metabolism</topic><topic>Carbachol - pharmacology</topic><topic>Cell Line, Transformed</topic><topic>Cell Shape</topic><topic>Claudin-1</topic><topic>Electric Impedance</topic><topic>Inflammation Mediators - metabolism</topic><topic>Interferon-gamma - metabolism</topic><topic>Membrane Proteins - metabolism</topic><topic>Muscarinic Agonists - pharmacology</topic><topic>Parotid Gland - cytology</topic><topic>Parotid Gland - drug effects</topic><topic>Parotid Gland - immunology</topic><topic>Parotid Gland - ultrastructure</topic><topic>Permeability</topic><topic>Rats</topic><topic>Receptors and Signal Transduction</topic><topic>Receptors, Purinergic P2 - metabolism</topic><topic>Receptors, Purinergic P2Y2</topic><topic>Saliva - metabolism</topic><topic>Tight Junctions - drug effects</topic><topic>Tight Junctions - immunology</topic><topic>Tight Junctions - ultrastructure</topic><topic>Time Factors</topic><topic>Tumor Necrosis Factor-alpha - metabolism</topic><topic>Uridine Triphosphate - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Baker, Olga J</creatorcontrib><creatorcontrib>Camden, Jean M</creatorcontrib><creatorcontrib>Redman, Robert S</creatorcontrib><creatorcontrib>Jones, Jonathan E</creatorcontrib><creatorcontrib>Seye, Cheikh I</creatorcontrib><creatorcontrib>Erb, Laurie</creatorcontrib><creatorcontrib>Weisman, Gary A</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>American Journal of Physiology: Cell Physiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Baker, Olga J</au><au>Camden, Jean M</au><au>Redman, Robert S</au><au>Jones, Jonathan E</au><au>Seye, Cheikh I</au><au>Erb, Laurie</au><au>Weisman, Gary A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Proinflammatory cytokines tumor necrosis factor-alpha and interferon-gamma alter tight junction structure and function in the rat parotid gland Par-C10 cell line</atitle><jtitle>American Journal of Physiology: Cell Physiology</jtitle><addtitle>Am J Physiol Cell Physiol</addtitle><date>2008-11-01</date><risdate>2008</risdate><volume>295</volume><issue>5</issue><spage>C1191</spage><epage>C1201</epage><pages>C1191-C1201</pages><issn>0363-6143</issn><eissn>1522-1563</eissn><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-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) 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-alpha and IFN-gamma 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 P2Y(2) nucleotide receptor agonist. In contrast, TNF-alpha and IFN-gamma had no effect on agonist-induced increases in the intracellular calcium concentration [Ca(2+)](i) in Par-C10 cells. Furthermore, treatment of Par-C10 cell monolayers with TNF-alpha and IFN-gamma 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-alpha, but not IFN-gamma, were reversible by incubation of Par-C10 cell monolayers with cytokine-free medium for 24 h, indicating that IFN-gamma 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.</abstract><cop>United States</cop><pub>American Physiological Society</pub><pmid>18768927</pmid><doi>10.1152/ajpcell.00144.2008</doi><oa>free_for_read</oa></addata></record> |
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subjects | Animals Calcium - metabolism Carbachol - pharmacology Cell Line, Transformed Cell Shape Claudin-1 Electric Impedance Inflammation Mediators - metabolism Interferon-gamma - metabolism Membrane Proteins - metabolism Muscarinic Agonists - pharmacology Parotid Gland - cytology Parotid Gland - drug effects Parotid Gland - immunology Parotid Gland - ultrastructure Permeability Rats Receptors and Signal Transduction Receptors, Purinergic P2 - metabolism Receptors, Purinergic P2Y2 Saliva - metabolism Tight Junctions - drug effects Tight Junctions - immunology Tight Junctions - ultrastructure Time Factors Tumor Necrosis Factor-alpha - metabolism Uridine Triphosphate - metabolism |
title | Proinflammatory cytokines tumor necrosis factor-alpha and interferon-gamma alter tight junction structure and function in the rat parotid gland Par-C10 cell line |
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