33
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      Proinflammatory cytokines disrupt epithelial barrier function by apoptosis-independent mechanisms.

      Read this article at

      ScienceOpenPublisherPubMed
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          It is well known that inflammatory conditions of the intestinal mucosa result in compromised barrier function. Inflammation is characterized by an influx into the mucosa of immune cells that influence epithelial function by releasing proinflammatory cytokines such as IFN-gamma and TNF-alpha. Mucosal barrier function is regulated by the epithelial apical junctional complex (AJC) consisting of the tight junction and the adherens junction. Since the AJC regulates barrier function, we analyzed the influence of IFN-gamma and TNF-alpha on its structure/function and determined the contribution of apoptosis to this process using a model intestinal epithelial cell line, T84, and IFN-gamma and TNF-alpha. AJC structure/function was analyzed by confocal microscopy, biochemical analysis, and physiologic measurement of epithelial gate/fence function. Apoptosis was monitored by determining cytokeratin 18 cleavage and caspase-3 activation. IFN-gamma induced time-dependent disruptions in epithelial gate function that were potentiated by coincubation with TNF-alpha. Tight junction fence function was somewhat disrupted. Cytokine treatment was associated with internalization of AJC transmembrane proteins, junction adhesion molecule 1, occludin, and claudin-1/4 with minimal effects on the cytoplasmic plaque protein zonula occludens 1. Detergent solubility profiles of junction adhesion molecule 1 and E-cadherin and their affiliation with "raft-like" membrane microdomains were modified by these cytokines. Inhibition of cytokine-induced apoptosis did not block induced permeability defects; further emphasizing their primary influence on the epithelial AJC structure and barrier function. Our findings for the first time clearly separate the proapoptotic effects of IFN-gamma and TNF-alpha from their abilities to disrupt barrier function.

          Related collections

          Author and article information

          Journal
          J Immunol
          Journal of immunology (Baltimore, Md. : 1950)
          The American Association of Immunologists
          0022-1767
          0022-1767
          Dec 01 2003
          : 171
          : 11
          Affiliations
          [1 ] Department of Pathology and Laboratory Medicine, Epithelial Pathobiology Research Unit, Emory University, Atlanta, GA, 30322, USA.
          Article
          10.4049/jimmunol.171.11.6164
          14634132
          dd016a90-e065-44b3-b5bf-df72bad9fa7f
          History

          Comments

          Comment on this article