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B Activation and Proinflammatory Gene Expression by Inhibiting Inhibitory Factor I-B Kinase Activity1
,
Departments of
*
Medicine, Microbiology, and Immunology,
Biochemistry and Biophysics, and
Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC 27599;
§
Department of Natural Sciences, Fayettsville State University, Fayettesville, NC, 28301; and
¶
Narula Research, Chapel Hill, NC 27516
NF-
B plays a critical role in the transcriptional regulation of
proinflammatory gene expression in various cells. Cytokine-mediated
activation of NF-B requires activation of various kinases, which
ultimately leads to the phosphorylation and degradation of IB, the
NF-B cytoplasmic inhibitor. The food derivative curcumin has been
shown to inhibit NF-B activity in some cell types. In this report we
investigate the mechanism of action of curcumin on cytokine-induced
proinflammatory gene expression using intestinal epithelial cells
(IEC). Curcumin inhibited IL-1ß-mediated ICAM-1 and IL-8 gene
expression in IEC-6, HT-29, and Caco-2 cells. Cytokine-induced NF-B
DNA binding activity, RelA nuclear translocation, IB
degradation,
IB serine 32 phosphorylation, and IB kinase (IKK) activity were
blocked by curcumin treatment. Wound-induced p38 phosphorylation was
not inhibited by curcumin treatment. In addition, mitogen-activated
protein kinase/ERK kinase kinase-1-induced IL-8 gene expression and
12-O-tetraphorbol 12-myristate 13-acetate-responsive
element-driven luciferase expression were inhibited by curcumin.
However, IB degradation induced by ectopically expressed
NF-B-inducing kinase or IKK was not inhibited by curcumin treatment.
Therefore, curcumin blocks a signal upstream of NF-B-inducing kinase
and IKK. We conclude that curcumin potently inhibits cytokine-mediated
NF-B activation by blocking a signal leading to IKK
activity.
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C. Jobin and R. B. Sartor The Ikappa B/NF-kappa B system: a key determinant of mucosal inflammation and protection Am J Physiol Cell Physiol, March 1, 2000; 278(3): C451 - C462. [Abstract] [Full Text] [PDF]
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R. J. Anto, T. T. Maliekal, and D. Karunagaran L-929 Cells Harboring Ectopically Expressed RelA Resist Curcumin-induced Apoptosis J. Biol. Chem., May 19, 2000; 275(21): 15601 - 15604. [Abstract] [Full Text] [PDF]
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