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TNF-alpha Activates MUC2 Transcription via NF-kappaB but Inhibits via JNK ActivationAhn D.-H.1 · Crawley S.C.1,2 · Hokari R.1 · Kato S.1 · Yang S.C.1 · Li J.-D.3 · Kim Y.S.1,2
1Gastrointestinal Research Laboratory, Veterans’ Affairs Medical Center, San Francisco, 2Department of Medicine, University of California, San Francisco, 3Gonda Department of Cell and Molecular Biology, House Ear Institute, University of Southern California, Los Angeles Corresponding Author
Young S. Kim
Department of Veterans’ Affairs Medical Center
4150 Clement St., San Francisco, California 94121 (USA)
Tel. +1 415-750-2095, Fax: +1 415-750-6972
The molecular mechanisms responsible for TNF-α-mediated MUC2 intestinal mucin up-regulation in HM3 colon adenocarcinoma cells were analyzed using promoter-reporter assays of the 5’-flanking region of the MUC2 gene. Chemical inhibitors, mutant reporter constructs, and EMSA confirmed I-kappaB/NF-kappaB pathway involvement. Wortmannin, LY294002 and dominant negative Akt, as well as dominant negative NF-kappaB-inducing kinase (NIK) inhibited MUC2 reporter transcription, indicating that both phosphatidylinositol-3-OH kinase (PI3K)/Akt signaling pathway and NIK pathways mediate the effects of TNF-alpha. Wortmannin inhibited NF-kappaB binding and transcriptional activity without inhibiting NF-kappaB translocation to the nucleus, indicating that PI3K/Akt signaling activates NF-kappaB transcriptional activity directly. Our results demonstrate that TNF-alpha up-regulates MUC2 in human colon epithelial cells via several signaling pathways, involving both NIK and PI3K/Akt, which converge at the common IKK/I-kappaB/NF-kappaB pathway. TNF-alpha activated JNK, but JNK inhibitor SP600125 and dominant negative cJun consistently activated transcription, revealing a negative role for this signaling pathway. Thus TNF-alpha causes a net up-regulation of MUC2 gene expression in cultured colon cancer cells because NF-kappaB transcriptional activation of this gene is able to counter-balance the suppressive effects of the JNK pathway. However, the existence of this inhibitory JNK pathways suggests a mechanism whereby - in the absence of NF-kappaB activation - TNF-alpha production during inflammation in vivo could actually inhibit MUC2 production, giving rise to the defective mucosal protection which characterizes inflammatory bowel disease.
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