Evidence of functional cross talk between the Notch and NF-κB pathways in nonneoplastic hyperproliferating colonic epithelium

Ahmed I, Roy B, Chandrakesan P, Venugopal A, Xia L, Jensen R, Anant S, Umar S. Evidence of functional cross talk between the Notch and NF-kappa B pathways in nonneoplastic hyperproliferating colonic epithelium. Am J Physiol Gastrointest Liver Physiol 304: G356-G370, 2013. First published November 29, 2012; doi: 10.1152/ajpgi.00372.2012.-The Notch and NF-kappa B signaling pathways regulate stem cell function and inflammation in the gut, respectively. We investigate whether a functional cross talk exists between the two pathways during transmissible murine colonic hyperplasia (TMCH) caused by Citrobacter rodentium (CR). During TMCH, NF-kappa B activity and subunit phosphorylation in colonic crypts of NIH Swiss mice at days 6 and 12 were associated with increases in downstream target CXC chemokine ligand (CXCL)-1/keratinocyte-derived chemokine (KC) expression. Blocking Notch signaling acutely for 5 days with the Notch blocker dibenzazepine (DBZ) failed to inhibit crypt NF-kappa B activity or CXCL-1/KC expression. Chronic DBZ administration for 10 days, however, blocked Notch and NF-kappa B signaling in the crypts and abrogated hyperplasia. Intriguingly, chronic Notch inhibition was associated with significant increases in IL-1 alpha, granulocyte colony-stimulating factor, monocyte chemoattractant protein 1, macrophage inflammatory protein 2, and KC in the crypt-denuded lamina propria or whole distal colon, with concomitant increases in myeloperoxidase activity. In core-3(-/-) mice, which are defective in intestinal mucin, DBZ administration replicated the results of NIH Swiss mice; in Apc(Min/+) mice, which are associated with CR-induced elevation of NF-kappa B-p65(276) expression, DBZ reversed the increase in NF-kappa B-p65(276), which may have blocked rapid proliferation of the mutated crypts. DBZ further blocked reporter activities involving the NF-kappa B-luciferase reporter plasmid or the Toll-like receptor 4/NF-kappa B/SEAPorter HEK-293 reporter cell line, while ectopic expression of Notch-N-ICD reversed the inhibitory effect. Dietary bael (Aegle marmelos) extract (4%) and curcumin (4%) restored Notch and NF-kappa B cross talk in NIH Swiss mice, inhibited CR/DBZ-induced apoptosis in the crypts, and promoted crypt regeneration. Thus functional cross talk between the Notch and NF-kappa B pathways during TMCH regulates hyperplasia and/or inflammation in response to CR infection.