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IFNg influences epithelial proliferation by modulating Aktbeta catenin signaling downstream of cadherins.
Author(s) -
Dominguez Porfirio Nava,
Kolegraff Keli N.,
Koch Stefan,
Parkos Charles,
Nusrat Asma
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.275.5
Subject(s) - microbiology and biotechnology , protein kinase b , cell growth , catenin , phosphorylation , barrier function , signal transduction , wnt signaling pathway , beta catenin , biology , chemistry , biochemistry
Intestinal mucosal inflammation in inflammatory bowel disease (IBD) is associated with perturbed intestinal epithelial homeostasis (proliferation/differentiation) and barrier function that are mediated, in part, by pro‐inflammatory cytokines such as IFNγ. However, the mechanisms governing IFNγ‐mediated regulation of epithelial homeostasis (proliferation/differentiation) and barrier function are not understood. Since a master regulator of epithelial homeostasis is E‐cadherin we investigated if IFNγ modulates epithelial homeostasis by regulating signaling proteins downstream of intestinal epithelial cadherins that also regulate cell proliferation. Using complementary in vitro and in vivo approaches, we identified protein kinase B (PKB/Akt) as a key protein that regulates stability of b‐catenin down‐stream of Ecadherin. IFNγ but not TNFα was observed to initially promote phosphorylation and activation of Akt and β‐catenin resulting in a burst of cell proliferation. However, sustained exposure to IFNγ induced stabilization of E‐cadherin and β‐catenin that was dependent on the cytoplasmic scaffold protein, 14‐3‐3ζ and Akt resulted in inhibition of β‐catenin induced cell proliferation. These results provide a novel paradigm through which sustained exposure to IFNγ results in inhibition β‐catenin signaling, reduced cell proliferation and barrier function in IBD. This work was supported by CCFA Fellowship and AGA Research Scholar Awards (PN) and NIH grants DK61379 (CP), DK55679 and DK59888 (AN).