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Article
Nature Cell Biology - 8, 1327 - 1336 (2006)
Published online: 26 November 2006; | doi:10.1038/ncb1500

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

Jongdae Lee1, Ji-Hun Mo1, Kyoko Katakura1, Irit Alkalay2, Adam N. Rucker1, Yu-Tsueng Liu1, Hyun-Ku Lee3, Carol Shen1, Gady Cojocaru2, Steve Shenouda1, Martin Kagnoff1, Lars Eckmann1, Yinon Ben-Neriah2 & Eyal Raz1

1  Department of Medicine, University of California, San Diego, La Jolla, CA 92093–0663, USA.

2  The Lautenberg Center for Immunology, Hebrew-University-Hadassah Medical School, Jerusalem 91120, Israel.

3  Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.

Correspondence should be addressed to Eyal Raz eraz@ucsd.edu or Jongdae Lee j142l33@ucsd.edu or Yinon Ben-Neriah yinon@cc.huji.ac.il

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.

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Nature Cell Biology
ISSN: 1465-7392
EISSN: 1476-4679
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