title: Involvement of heat shock protein a4/apg-2 in refractory inflammatory bowel disease.
abstract: BACKGROUND
  Expression of heat shock protein A4 (HSPA4, also called Apg-2), a member of the HSP110 family, is induced by several forms of stress. The physiological and pathological functions of HSPA4 in the intestine remain to be elucidated.
  
  
  METHODS
  We assessed HSPA4 expression and function by generating HSPA4-deficient 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 HSPA4 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 HSPA4 and Bcl-2 was increased in inflammatory cells of colonic mucosae. HSPA4 was overexpressed both in cancer cells and immune cells of human colorectal cancers. Patients with high expression of HSPA4 or Bmi1 showed significantly lower response rates upon subsequent steroid therapy as compared with patients with low expression of each gene. HSPA4-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 HSPA4 would control apoptosis of inflammatory cells and immune response in the gut, which might develop treatment resistance in IBD. HSPA4 and Bmi1 would be a useful biomarker for refractory clinical course and a promising approach for a therapeutic strategy in patients with IBD.
authors.affiliation: Departments of *Gastroenterology and Hepatology, and †Biochemistry, Kinki University Faculty of Medicine, Osaka-Sayama, Japan; and ‡Center for Innovation in Immunoregulative Technology and Therapeutics, and §Department of Clinical Molecular Biology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Teppei
authors.initials: T
authors.lastname: Adachi
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Sakurai
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kashida
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Mine
authors.forename: Satoru
authors.initials: S
authors.lastname: Hagiwara
authors.forename: Shigenaga
authors.initials: S
authors.lastname: Matsui
authors.forename: Koji
authors.initials: K
authors.lastname: Yoshida
authors.forename: Naoshi
authors.initials: N
authors.lastname: Nishida
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Watanabe
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Itoh
authors.forename: Jun
authors.initials: J
authors.lastname: Fujita
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Kudo
mesh_terms: D000818:Animals; D017209:Apoptosis; D016022:Case-Control Studies; D002478:Cells, Cultured; D003093:Colitis, Ulcerative / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D003424:Crohn Disease / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D004351:Drug Resistance / Q000276:immunology*; D004622:Embryo, Mammalian / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005500:Follow-Up Studies; D050957:HSP110 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D006801:Humans; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism; D053759:Interleukin-23 / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D011446:Prospective Studies; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D013256:Steroids / Q000494:pharmacology
chemical_list: C069077:BMI1 protein, human; C489421:Bmi1 protein, mouse; D016207:Cytokines; D050957:HSP110 Heat-Shock Proteins; C121993:HSPA4 protein, human; C485680:Hspa4 protein, mouse; D020381:Interleukin-17; D053759:Interleukin-23; D011518:Proto-Oncogene Proteins; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D013256:Steroids; D016264:Dextran Sulfate; D063150:Polycomb Repressive Complex 1