Korean J Anat.  2004 Dec;37(6):571-577.

Heme Oxygenase-1 is Involved in the Down-regulation of Nuclear Transcription Factor kappa B Activation in the Colonic Epithelium During Inflammation

• Yun KJ
• Kim YR
• Lee HJ
• Kim KS
• Kwon YM
• Choi MK
• Oh JM
• Chung YT

Abstract

Heme oxygenase-1 (HO-1) is a stress-inducible enzyme with anti-inflammatory activity, but the mechanisms underlying this activity are incompletely understood. Nuclear transcription factor kappa B (NF-kappa B) activation is an important factor in the pathogenesis of inflammatory bowel disease (IBD). We investigated the suppressive effects of HO-1 on the activation of NF-kappa B by pro-inflammatory cytokines in cultured colonic epithelial cells and by trinitrobenzene sulfonic acid (TNBS) in the colon of mice. The expression level of HO-1 in the colonic epithelium of a patient with inflammatory bowel disease and pseudo-membranous colitis was lower than that in a healthy control subject. In cultured human colonic epithelial HT-29 cells, pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha ) and IL-1 beta down-regulate HO-1 expression. The HO-1 inducer, cobalt protoporphyrin IX (CoPPIX), dramatically down-regulated NF-kappa B activation in HT-29 cells by TNF-alpha. In addition, bilirubin-a product of heme catabolism by HO-1-and the carbon monoxide donor tricarbonyldichlororuthenium (II) dimer also suppressed NF-kappa B activation by TNF-alpha. However, iron, another heme metabolite, did not suppress NF-kappa B activation by TNF-alpha. Furthermore, CoPPIX diminished the macroscopic and histopathological symptoms of TNBS-induced colitis and down-regulated NF-kappa B activation in mice. In conclusion, this study suggests that HO-1 plays an important role in the down-regulation of NF-kappa B activation, which is a key factor in the pathogenesis of IBD and is thus an excellent therapeutic target for the treatment of IBD.

Keyword

Cobalt protoporphyrin IX; Heme oxygenase-1; Nuclear transcription factor kappa B; Trinitrobenzene sulfonic acid; Colitis

MeSH Terms

Animals
Carbon Monoxide
Cobalt
Colitis
Colon*
Cytokines
Down-Regulation*
Epithelial Cells
Epithelium*
Heme Oxygenase-1*
Heme*
HT29 Cells
Humans
Inflammation*
Inflammatory Bowel Diseases
Interleukin-1beta
Iron
Metabolism
Mice
NF-kappa B
Tissue Donors
Transcription Factors*
Tumor Necrosis Factor-alpha
Carbon Monoxide
Cobalt
Cytokines
Heme
Heme Oxygenase-1
Interleukin-1beta
Iron
NF-kappa B
Transcription Factors
Tumor Necrosis Factor-alpha