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.
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: Donna L Arvans; Stephan R Vavricka; Hongyu Ren; Mark W Musch; Lisa Kang; Flavio G Rocha; Alvaro Lucioni; Jerrold R Turner; John Alverdy; Eugene B Chang Journal: Am J Physiol Gastrointest Liver Physiol Date: 2004-11-04 Impact factor: 4.052
Authors: Mikihiro Fujiya; Mark W Musch; Yasushi Nakagawa; Shien Hu; John Alverdy; Yutaka Kohgo; Olaf Schneewind; Bana Jabri; Eugene B Chang Journal: Cell Host Microbe Date: 2007-06-14 Impact factor: 21.023
Authors: Arkady Khoutorsky; Robert E Sorge; Masha Prager-Khoutorsky; Sophie Anne Pawlowski; Geraldine Longo; Seyed Mehdi Jafarnejad; Soroush Tahmasebi; Loren J Martin; Mark H Pitcher; Christos G Gkogkas; Reza Sharif-Naeini; Alfredo Ribeiro-da-Silva; Charles W Bourque; Fernando Cervero; Jeffrey S Mogil; Nahum Sonenberg Journal: Proc Natl Acad Sci U S A Date: 2016-10-03 Impact factor: 11.205
Authors: Shien Hu; Xiaorong Zhu; Joseph R Triggs; Yun Tao; Yunwei Wang; Lev Lichtenstein; Marc Bissonnette; Mark W Musch; Eugene B Chang Journal: Am J Physiol Gastrointest Liver Physiol Date: 2009-03-19 Impact factor: 4.052