Article abstract
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
Abstract
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-
B activation and cDNA microarray analysis. Whereas basolateral TLR9 signals IB
degradation and activation of the NF-B pathway, apical TLR9 stimulation invokes a unique response in which ubiquitinated IB accumulates in the cytoplasm preventing NF-B 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-B 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.
- Department of Medicine, University of California, San Diego, La Jolla, CA 92093–0663, USA.
- The Lautenberg Center for Immunology, Hebrew-University-Hadassah Medical School, Jerusalem 91120, Israel.
- Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Correspondence to: Eyal Raz1 e-mail: eraz@ucsd.edu
Correspondence to: Jongdae Lee1 e-mail: j142l33@ucsd.edu
Correspondence to: Yinon Ben-Neriah2 e-mail: yinon@cc.huji.ac.il
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