Mechanisms of Cross Hyporesponsiveness to Toll-Like Receptor Bacterial Ligands in Intestinal Epithelial Cells

Jan Michel Otte, Elke Cario, Daniel K. Podolsky

Research output: Contribution to journalArticlepeer-review

389 Scopus citations

Abstract

Background & Aims: Despite the ability to participate in immune responses and the continuous presence of bacteria and bacterial products, functional responses of intestinal epithelial cells (IEC) seem to be muted. Previously, tolerance to Toll-like receptors (TLRs) ligands has been described in monocytic cells. However, mechanisms in the intestine are unknown. Methods: The effect of purified lipopolysaccharide (LPS) and lipoteichoicacid (LTA) on expression and function of TLRs in intestinal epithelial cells (Colo205, SW480, T84) was assessed by Northern and Western blot and FACS analysis, kinase activity assays, immunohistochemistry, and ELISA. Results: Expression of TLRs except 10 was detected in primary IEC and TLR1-10 in the cultured cells. Short-term stimulation with LPS or LTA activated proinflammatory signaling cascades in IEC, including phosphorylation of IRAK and MAP kinases and increased IL-8 secretion, whereas prolonged incubation resulted in a state of hyporesponsiveness with no reactivation of the cells by a second challenge with either substance detected. The cells remained responsive to tumor necrosis factor (TNF). Hyporesponsive cells showed no alteration in expression of TLR or signaling molecules but revealed a decrease in TLR surface expression and IRAK activity. Toll-interacting protein (Tollip) mRNA and protein expression were increased in hyporesponsive cells, and overexpression of Tollip in IEC resulted in a significantly decreased proinflammatory response. Conclusions: Continuous presence of specific bacterial components results in a status of hyporesponsiveness in otherwise reactive IEC. Down-regulation of TLR surface expression and up-regulation of inhibitory Tollip with decreased phosphorylation of IRAK might all contribute to this hyporesponsiveness.

Original languageEnglish (US)
Pages (from-to)1054-1070
Number of pages17
JournalGastroenterology
Volume126
Issue number4
DOIs
StatePublished - Apr 2004

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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