TLR signaling at the intestinal epithelial interface

Maria T. Abreu, Lisa S. Thomas, Elizabeth T. Arnold, Katie Lukasek, Kathrin S. Michelsen, Moshe Arditi

Research output: Contribution to journalArticle

97 Scopus citations

Abstract

The intestinal epithelium provides a critical interface between lumenal bacteria and the mucosal immune system. Whereas normal commensal flora do not trigger acute inflammation, pathogenic bacteria trigger a potent inflammatory response. Our studies emanate from the hypothesis that the intestinal epithelium is normally hyporesponsive to commensal pathogen-associated molecular patterns (PAMPs) such as LPS. Our data demonstrate that normal human colonic epithelial cells and lamina propria cells express low levels of TLR4 and its co-receptor MD-2. This expression pattern is mirrored by intestinal epithelial cell (IEC) lines. Co-expression of TLR4 and MD-2 is necessary and sufficient for LPS responsiveness in IEC. Moreover, LPS sensing occurs along the basolateral membrane of polarized IEC in culture. Expression of MD-2 is regulated by IFN-γ. Cloning of the MD-2 promoter demonstrates that promoter activity is increased by IFN-γ and blocked by the STAT inhibitor SOCS3. We conclude from our studies that the intestinal epithelium down-regulates expression of TLR4 and MD-2 and is LPS unresponsive. The Th1 cytokine IFN-γ up-regulates expression of MD-2 in a STAT-dependent fashion. The results of our studies have important implications for understanding human inflammatory bowel diseases.

Original languageEnglish (US)
Pages (from-to)322-331
Number of pages10
JournalJournal of Endotoxin Research
Volume9
Issue number5
DOIs
StatePublished - 2003

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Molecular Biology
  • Cell Biology
  • Infectious Diseases

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    Abreu, M. T., Thomas, L. S., Arnold, E. T., Lukasek, K., Michelsen, K. S., & Arditi, M. (2003). TLR signaling at the intestinal epithelial interface. Journal of Endotoxin Research, 9(5), 322-331. https://doi.org/10.1179/096805103225002593