Involvement of heat shock protein a4/apg-2 in refractory inflammatory bowel disease.

BACKGROUND:Expression of heat shock protein A4 also called Apg-2), a member of the HSP110 family, is induced by several forms of stress. The physiological and pathological functions of in the intestine remain to be elucidated. METHODS:We assessed Hduanyu18424 expression and function by generating mice and using 214 human intestinal mucosa samples from patients with inflammatory bowel disease (IBD). RESULTS:In the colonic mucosa of patients with IBD, a significant correlation was observed between the expression of Hduanyu18424 and antiapoptotic protein Bcl-2, a T-cell-derived cytokine IL-17 or stem cell markers, such as Sox2. In refractory ulcerative colitis, a condition associated with increased cancer risk, expression of Hduanyu18424 and Bcl-2 was increased in inflammatory cells of colonic mucosae. Hduanyu18424 was overexpressed both in cancer cells and immune cells of human colorectal cancers. Patients with high expression of Hduanyu18424 or Bmi1 showed significantly lower response rates upon subsequent steroid therapy as compared with patients with low expression of each gene. Hduanyu18424-deficient mice exhibit more apoptosis and less expression of IL-17/IL-23 in inflammatory cells and less number of Sox2 cells after administration of dextran sodium sulfate than control mice. Transduction of HspaA4 bone marrow into wild-type mice reduced the immune response. CONCLUSIONS:Upregulation of Bcl-2 and IL-17 by Hduanyu18424 would control apoptosis of inflammatory cells and immune response in the gut, which might develop treatment resistance in IBD. Hduanyu18424 and Bmi1 would be a useful biomarker for refractory clinical course and a promising approach for a therapeutic strategy in patients with IBD.

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