title: Maintenance of colonic homeostasis by distinctive apical TLR9 signalling in intestinal epithelial cells.
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-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.
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093-0663, USA. j142l33@ucsd.edu
authors.forename: Jongdae
authors.initials: J
authors.lastname: Lee
authors.forename: Ji-Hun
authors.initials: JH
authors.lastname: Mo
authors.forename: Kyoko
authors.initials: K
authors.lastname: Katakura
authors.forename: Irit
authors.initials: I
authors.lastname: Alkalay
authors.forename: Adam N
authors.initials: AN
authors.lastname: Rucker
authors.forename: Yu-Tsueng
authors.initials: YT
authors.lastname: Liu
authors.forename: Hyun-Ku
authors.initials: HK
authors.lastname: Lee
authors.forename: Carol
authors.initials: C
authors.lastname: Shen
authors.forename: Gady
authors.initials: G
authors.lastname: Cojocaru
authors.forename: Steve
authors.initials: S
authors.lastname: Shenouda
authors.forename: Martin
authors.initials: M
authors.lastname: Kagnoff
authors.forename: Lars
authors.initials: L
authors.lastname: Eckmann
authors.forename: Yinon
authors.initials: Y
authors.lastname: Ben-Neriah
authors.forename: Eyal
authors.initials: E
authors.lastname: Raz
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D016764:Cell Polarity; D002738:Chloroquine / Q000494:pharmacology; D003106:Colon / Q000166:cytology* / Q000187:drug effects / Q000473:pathology; D020895:Enterocytes / Q000166:cytology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051217:Toll-Like Receptor 9 / Q000737:chemistry / Q000378:metabolism*
chemical_list: D008024:Ligands; D012333:RNA, Messenger; D051217:Toll-Like Receptor 9; D002738:Chloroquine