Inflammation-induced, 3'UTR-dependent translational inhibition of Hsp70 mRNA impairs intestinal homeostasis.
Although the inducible heat shock protein 70 (Hsp70) is essential for maintaining intestinal homeostasis in colitis, it is translationally downregulated in inflamed colonic mucosa, paradoxically rendering the gut more susceptible to injury. We examined the basis for this process by analyzing the role of untranslated regions (UTR) of Hsp70 mRNA in inflammation-associated downregulation in vitro and in vivo. Using luciferase-reporter assays in young adult mouse intestinal epithelial cells, we determined that cytokine-induced translational inhibition of Hsp70 mRNA was mediated by the 3'UTR, but not 5'UTR. In vivo, dextran sodium sulfate (DSS) colitis was induced in wild-type (WT) and villin-promoter regulated "UTR-less" Hsp70 transgenic (TG) mice, the latter exhibiting intestinal epithelial-specific transgene expression. Progressive downregulation of colonic Hsp70 protein expression was observed in WT, but not in TG, mice with increasing severity of mucosal inflammation, confirming the essential role of the 3'UTR in mediating inflammation-associated downregulation of Hsp70. Hsp70 TG mice demonstrated significantly lower endoscopic and histological inflammation scores in DSS-induced colitis than WT. In conclusion, downregulation of Hsp70 expression in inflamed mucosa is mediated by translational inhibition requiring the 3'UTR, resulting in increased mucosal injury. By forcing intestinal epithelial-specific Hsp70 expression in vivo, the severity of experimentally induced colitis was significantly reduced.
Hu
Shien
S
The Martin Boyer Laboratories, Department of Medicine, University of Chicago IBD Research Center, Chicago, Illinois 60637, USA.
Zhu
Xiaorong
X
Triggs
Joseph R
JR
Tao
Yun
Y
Wang
Yunwei
Y
Lichtenstein
Lev
L
Bissonnette
Marc
M
Musch
Mark W
MW
Chang
Eugene B
EB
D020413:3' Untranslated Regions; D000818:Animals; D002460:Cell Line; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003106:Colon / Q000378:metabolism* / Q000503:physiopathology; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D015536:Down-Regulation; D017930:Genes, Reporter; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D014176:Protein Biosynthesis; D012720:Severity of Illness Index; D013997:Time Factors; D014162:Transfection
D020413:3' Untranslated Regions; D016207:Cytokines; D018840:HSP70 Heat-Shock Proteins; D016264:Dextran Sulfate