Curcumin blocks cytokine-mediated NF-kappa B activation and proinflammatory gene expression by inhibiting inhibitory factor I-kappa B kinase activity

• Published in: The Journal of immunology (1950) Vol. 163; no. 6; pp. 3474 - 3483
• Main Authors: Jobin, C, Bradham, C A, Russo, M P, Juma, B, Narula, A S, Brenner, D A, Sartor, R B
• Format: Journal Article
• Language: English
• Published: United States 15.09.1999
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Cell Line; Curcumin - pharmacology; Cytokines - physiology; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - metabolism; Enzyme Activation - drug effects; Enzyme Inhibitors - pharmacology; Gene Expression Regulation - drug effects; HT29 Cells; Humans; I-kappa B Kinase; I-kappa B Proteins; Inflammation - enzymology; Inflammation - genetics; Inflammation - metabolism; Intercellular Adhesion Molecule-1 - biosynthesis; Intercellular Adhesion Molecule-1 - genetics; Interleukin-8 - biosynthesis; Interleukin-8 - genetics; Intestinal Mucosa - drug effects; Intestinal Mucosa - enzymology; Intestinal Mucosa - metabolism; Intestinal Mucosa - pathology; MAP Kinase Kinase Kinase 1; NF-kappa B - antagonists & inhibitors; NF-kappa B - metabolism; Phosphorylation; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - metabolism; Protein-Serine-Threonine Kinases - physiology; Rats; Signal Transduction - drug effects; Signal Transduction - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.163.6.3474

NF-kappa B plays a critical role in the transcriptional regulation of proinflammatory gene expression in various cells. Cytokine-mediated activation of NF-kappa B requires activation of various kinases, which ultimately leads to the phosphorylation and degradation of I kappa B, the NF-kappa B cytoplasmic inhibitor. The food derivative curcumin has been shown to inhibit NF-kappa 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-1 beta-mediated ICAM-1 and IL-8 gene expression in IEC-6, HT-29, and Caco-2 cells. Cytokine-induced NF-kappa B DNA binding activity, RelA nuclear translocation, I kappa B alpha degradation, I kappa B serine 32 phosphorylation, and I kappa B 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, I kappa B alpha degradation induced by ectopically expressed NF-kappa B-inducing kinase or IKK was not inhibited by curcumin treatment. Therefore, curcumin blocks a signal upstream of NF-kappa B-inducing kinase and IKK. We conclude that curcumin potently inhibits cytokine-mediated NF-kappa B activation by blocking a signal leading to IKK activity.