Inflammation-induced, 3′UTR-dependent translational inhibition of Hsp70 mRNA impairs intestinal homeostasis

Abstract

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.

Expression of heat shock proteins 27 and 72 correlates with specific commensal microbes in different regions of porcine gastrointestinal tract

“…It was recently reported that adult female pigs with lower levels of F. prausnizii and branched-chain fatty acids in colon content showed a higher sensitivity of the colonic mucosa to inflammatory and oxidative stresses although HSP levels were not significantly decreased (7). These results, as well as those reported by others (3,20,39), indicate that specific commensal microbes can influence host immune compartments distinctively.…”

“…Enhanced epithelial expression of HSP70 in Crohn's disease and ulcerative colitis, independent on the degree of inflammation, has been reported (30). In contrast, more recent data show that the expression of HSPs decreased in inflammatory conditions such as IBD, indicating that they are required in maintaining intestinal homeostasis (20). In the healthy porcine gut, we found a pattern in expression of both HSP27 and HSP72 along the villus/crypt axis, with the highest expression at the surface epithelium, lowest expression in crypt cells, and limited expression in the lamina propria.…”

Gut epithelial inducible heat-shock proteins and their modulation by diet and the microbiota

“…32 The 3 0 untranslated region (3 0 -UTR)-dependent translational inhibition of HSP70 mRNA was then demonstrated in ulcerative colitis. 99 However, one study reported tissue iHSP70 protein concentrations to be higher at the time of disease diagnosis and to decrease after treatment. 100 Animal models of gut inflammation.…”

Stress granule formation mediates the inhibition of colonic Hsp70 translation by interferon-γ and tumor necrosis factor-α

“…INTESTINAL HEAT SHOCK PROTEINS are highly conserved, multifunctional proteins essential for maintenance of gut health, and their altered expression can render the mucosa more susceptible to sustained and severe injury and possibly malignant transformation (4,8,9,16,21,30). These proteins, particularly Hsp70 and Hsp25, are highly regulated by a complex set of extracellular cues, including gut-derived microbial signals such as LPS and short-chain fatty acids (SCFAs) (2,14,15,23,26).…”

“…We have previously shown that this effect is in part mediated by the increased levels of proinflammatory cytokines such as interferon-␥ (IFN-␥) and tumor necrosis factor-␣ (TNF-␣) that stimulate a translational downregulation of Hsp70. These cytokines stimulate the phosphorylation of the RNA-dependent protein kinase (PKR), which in turn phosphorylates eukaryotic initiation factor-␣ (eIF-2␣), resulting in reduced Hsp70 protein translation in inflammatory bowel diseases and experimental colitis (8,9).…”