TITLE

EFFECTS OF NICOTINE ON SPONTANEOUS AND LPS-INDUCED NF-κB ACTIVATION AND APOPTOSIS IN COLORECTAL CELLS: RELEVANCE TO INFLAMMATORY BOWEL DISEASE?

AUTHOR(S)
Aldhous, M.C.; Stark, L.A.; Dunlop, M.G.; Satsangi, J.
PUB. DATE
April 2003
SOURCE
Gut;Apr2003 Supplement 1, Vol. 52, pA62
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Background: Complex genetic, environmental, and immunological interactions are involved in the pathogenesis of Crohn's disease (CD). Mutations within the NOD-2 gene are present on up to 50% of patients with CD and clearly influence disease susceptibility and behaviour. Early functional data implicate NOD-2 as an intracellular sensor of bacterial Jipopolysaccharide (LPS) which directly influences NF-κB activation. Cigarette smoking is the best defined environmental risk factor for CD. While nicotine therapy has had limited success in ulcerative colitis, it is not clear whether nicotine itself causes the increased severity of CD, nor whether nicotine supplements could be used to aid patients stop smoking. Methods and Results: We have examined the effect of nicotine on NF-κB activation in SW480 colorectal cancer ceils. Immunohistochemistry for NF-κB (p65) expression showed a dose-dependent increase in NF-κB activation after 30 minutes with nicotine alone, which was reversed by addition of LPS. Cells stimulated overnight with nicotine and/or LPS, showed a dose-dependent decrease in apoptosis with nicotine alone, which was modified by LPS. In kinetic studies using western blot analysis, nicotine induced degradation of the NF-κB inhibitor protein, I-κB, within 1 hour and levels returned to baseline by 5 hours. Pre-incubation with nicotine for 1-5 hours inhibited I-κB degradation in response to LPS. Conclusions: These data indicate that nicotine directly influences NF-κB activity and suggest that nicotine may modify cellular responses to LPS. The consequent effects on cytokine production and apoptosis may help explain the effects of smoking in CD and have implications for the use of nicotine in smoking cessation therapy.
ACCESSION #
9747703

 

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