Maintenance of colonic homeostasis by distinctive apical TLR9 signalling in intestinal epithelial cells

Nat Cell Biol. 2006 Dec;8(12):1327-36. doi: 10.1038/ncb1500. Epub 2006 Nov 26.


The mechanisms by which commensal bacteria suppress inflammatory signalling in the gut are still unclear. Here, we present a cellular mechanism whereby the polarity of intestinal epithelial cells (IECs) has a major role in colonic homeostasis. TLR9 activation through apical and basolateral surface domains have distinct transcriptional responses, evident by NF-kappaB activation and cDNA microarray analysis. Whereas basolateral TLR9 signals IkappaBalpha degradation and activation of the NF-kappaB pathway, apical TLR9 stimulation invokes a unique response in which ubiquitinated IkappaB accumulates in the cytoplasm preventing NF-kappaB activation. Furthermore, apical TLR9 stimulation confers intracellular tolerance to subsequent TLR challenges. IECs in TLR9-deficient mice, when compared with wild-type and TLR2-deficient mice, display a lower NF-kappaB activation threshold and these mice are highly susceptible to experimental colitis. Our data provide a case for organ-specific innate immunity in which TLR expression in polarized IECs has uniquely evolved to maintain colonic homeostasis and regulate tolerance and inflammation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caco-2 Cells
  • Cell Polarity*
  • Chloroquine / pharmacology
  • Colon / cytology*
  • Colon / drug effects
  • Colon / pathology
  • Enterocytes / cytology*
  • Gene Expression Regulation / drug effects
  • Homeostasis* / drug effects
  • Humans
  • Immune Tolerance / drug effects
  • Ligands
  • Mice
  • Mice, Inbred C57BL
  • Protein Structure, Tertiary
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Signal Transduction* / drug effects
  • Toll-Like Receptor 9 / chemistry
  • Toll-Like Receptor 9 / metabolism*


  • Ligands
  • RNA, Messenger
  • Toll-Like Receptor 9
  • Chloroquine