title: Evidence of functional cross talk between the Notch and NF-κB pathways in nonneoplastic hyperproliferating colonic epithelium.
abstract: The Notch and NF-κB 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-κB 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-κB activity or CXCL-1/KC expression. Chronic DBZ administration for 10 days, however, blocked Notch and NF-κB signaling in the crypts and abrogated hyperplasia. Intriguingly, chronic Notch inhibition was associated with significant increases in IL-1α, 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-κB-p65(276) expression, DBZ reversed the increase in NF-κB-p65(276), which may have blocked rapid proliferation of the mutated crypts. DBZ further blocked reporter activities involving the NF-κB-luciferase reporter plasmid or the Toll-like receptor 4/NF-κB/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-κB 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-κB pathways during TMCH regulates hyperplasia and/or inflammation in response to CR infection.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Ishfaq
authors.initials: I
authors.lastname: Ahmed
authors.forename: Badal
authors.initials: B
authors.lastname: Roy
authors.forename: Parthasarathy
authors.initials: P
authors.lastname: Chandrakesan
authors.forename: Anand
authors.initials: A
authors.lastname: Venugopal
authors.forename: Lijun
authors.initials: L
authors.lastname: Xia
authors.forename: Roy
authors.initials: R
authors.lastname: Jensen
authors.forename: Shrikant
authors.initials: S
authors.lastname: Anant
authors.forename: Shahid
authors.initials: S
authors.lastname: Umar
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D018925:Chemokines / Q000096:biosynthesis; D044082:Citrobacter rodentium; D003092:Colitis / Q000209:etiology / Q000503:physiopathology*; D003106:Colon / Q000187:drug effects; D003474:Curcumin / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis; D003984:Dibenzazepines / Q000494:pharmacology; D004756:Enterobacteriaceae Infections / Q000503:physiopathology*; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D051880:Receptors, Notch / Q000187:drug effects / Q000502:physiology*
chemical_list: D018925:Chemokines; D016207:Cytokines; D003984:Dibenzazepines; D016328:NF-kappa B; D051880:Receptors, Notch; D003474:Curcumin; C527817:dibenzazepine