Translational inhibition of colonic epithelial heat shock proteins by IFN-gamma and TNF-alpha in intestinal inflammation.

Abstract

BACKGROUND & AIMS:

Inducible heat shock proteins (iHsp), Hsp25/27 and Hsp70, play essential roles in protecting cells against stress and, in intestinal mucosal inflammation, potentially lessening the extent and severity of injury. We examined the expression and regulation of iHsp in human and experimental inflammatory bowel diseases (IBD) and in vitro.

METHODS:

iHsp expression and regulation were assessed in normal and IBD colonic biopsy specimens, IL-10(-/-) mice, and young adult mouse colonic epithelial cells by immunohistochemistry, Western blot, and real-time polymerase chain reaction (PCR). Phosphorylation of double-stranded RNA-dependent protein kinase (PKR) and eukaryotic initiation factor-2alpha (eIF-2alpha) was determined by Western blot.

RESULTS:

Hsp25/27 and Hsp70 levels were selectively reduced in areas of active mucosal inflammation associated with human IBD and IL-10(-/-) mice with colitis. Wild-type mice treated in vivo with interferon (IFN)-gamma + tumor necrosis factor (TNF)-alpha also demonstrated reduced colonic Hsp25/27 and Hsp70. In young adult mouse colonic epithelial cells, IFN-gamma+TNF-alpha inhibited heat induction of Hsp25/27 and Hsp70, an effect not associated with changes in iHsp messenger RNA or protein half-lives but caused by suppressed de novo iHsp synthesis. IFN-gamma+TNF-alpha cotreatment activated PKR, resulting in phosphorylation and inactivation of eIF-2alpha, an essential factor in protein translation. These effects were not due to induced apoptosis and could be negated by PKR-inhibitor and short interfering RNA to PKR. Increased phosphorylation of PKR and eIF-2alpha were also observed in active IBD tissues.

CONCLUSIONS:

Mucosal inflammation is associated with iHsp down-regulation, an effect that appears mediated by translational down-regulation by proinflammatory cytokines. In the context of IBD, we propose that this mechanism contributes to the severity, extent, and persistence of inflammation-induced mucosal injury.

• Authors: Shien Hu, Mae J Ciancio, Maor Lahav, Mikihiro Fujiya, Lev Lichtenstein, Shrikant Anant, Mark W Musch, Eugene B Chang
• Journal: Gastroenterology (Gastroenterology) Vol. 133 Issue 6 Pg. 1893-904 (Dec 2007) ISSN: 1528-0012 [Electronic] United States
• PMID: 18054561 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• HSP70 Heat-Shock Proteins
• Heat-Shock Proteins
• Hsbp1 protein, mouse
• Molecular Chaperones
• Neoplasm Proteins
• Tumor Necrosis Factor-alpha
• Interferon-gamma

Topics

• Animals
• Apoptosis (immunology)
• Cells, Cultured
• Colitis, Ulcerative (immunology)
• Colon (immunology)
• Crohn Disease (immunology)
• Disease Models, Animal
• Down-Regulation
• HSP70 Heat-Shock Proteins (immunology)
• Heat-Shock Proteins (immunology)
• Humans
• Inflammatory Bowel Diseases (immunology)
• Interferon-gamma (immunology)
• Intestinal Mucosa (immunology)
• Male
• Mice
• Mice, Inbred C57BL
• Molecular Chaperones
• Neoplasm Proteins (immunology)
• Protein Biosynthesis (immunology)
• Tumor Necrosis Factor-alpha (immunology)