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

J Immunol. 1999 Sep 15;163(6):3474-83.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 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

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Cytokines
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • I-kappa B Proteins
  • Interleukin-8
  • NF-kappa B
  • Intercellular Adhesion Molecule-1
  • Protein-Serine-Threonine Kinases
  • CHUK protein, human
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human
  • MAP Kinase Kinase Kinase 1
  • MAP3K1 protein, human
  • Curcumin