Visit our Expo - Redox and Inflammation signaling 2012

Tissue specific control of NF-kB activation
Yinon Ben-Neriah1, Jongdae Lee2, Elad Horwitz1, Gady Cojocaru1, Naama Kanarik1,
Matti Davis1, Irit Alkalay1, Kyoko Katakura2, Lars Eckmann2, Eli Pikarsky3 and Eyal
Raz2
1The Lautenberg Center for Immunology and 3Dept of Pathology, Hebrew-University-
Hadassah Medical School Jerusalem 91120, Israel; 2Department of Medicine University
of California San Diego, La Jolla, CA 92093-0663
Canonical NF-kB activation targets IkB and p105/NF-kB1 to degradation via the ubiquitin
proteasome system. We and others have previously shown that #-TrCP is a key regulator in
this system; its two isoforms #-TrCP1 and 2 are both necessary and sufficient to control IkB
stability. Ongoing experiments in our lab attempt to unveil the unique functions of each #-
TrCP isoform in different tissues and determine the consequence of specific isoform
inhibition. So far, #-TrCP-controlled degradation has been mainly studied in standard tissue
culture conditions, yet many tissues and particularly epithelial cells are configured in vivo in a
specific orientation. We will describe a cellular mechanism whereby the polarity of gut
epithelium dictates the outcome of NF-kB signaling, thereby playing a major role in colonic
homeostasis. TLR9 activation via apical and basolateral surface domains have distinct
transcriptional responses. Whereas basolateral TLR9 signals NF-kB activation, apical TLR9
invokes intracellular tolerance against subsequent basolateral TLR9 and other TLRs'
challenges. TLR9-deficient mice lacking the tolerizing receptor are triggered much more
rapidly for NF-kB activation and are highly susceptible to experimental colitis. Our data
provide a case for an organ-specific innate immunity where TLR regulation evolved to
maintain colonic homeostasis. This is achieved by a novel cellular mechanism, where the
different surface domains of a polarized cell dictate an opposing signaling outcome to a
similar stimulus.
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