Open AccessPKR protects colonic epithelium against colitis through the unfolded protein response and prosurvival signaling
Author(s) -
Cao Stewart Siyan,
Song Benbo,
Kaufman Randal J.
Publication year - 2012
Publication title -
inflammatory bowel diseases
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.932
H-Index - 146
eISSN - 1536-4844
pISSN - 1078-0998
DOI - 10.1002/ibd.22878
Subject(s) - protein kinase r , signal transduction , protein kinase b , phosphorylation , microbiology and biotechnology , pi3k/akt/mtor pathway , eif 2 kinase , protein kinase a , biology , cancer research , chemistry , cyclin dependent kinase 2
Background: The dsRNA‐activated protein kinase (PKR) phosphorylates the α subunit of eukaryotic translation initiation factor 2 (eIF2α), a global regulator of protein synthesis in mammals. In addition, PKR activates several signal transduction pathways including STAT3 and AKT. PKR is activated by a number of inflammatory stimuli that are induced in the inflamed intestine. In this study we intended to determine the role of PKR in colonic epithelial cells during experimental colitis in mice. Methods: Age‐ and sex‐matched PKR +/+,+/− and PKR −/− littermate mice were reconstituted with wildtype bone marrow cells and subjected to dextran sodium sulfate (DSS)‐induced colitis. Results: PKR −/− mice displayed more severe clinical and histological manifestations upon DSS colitis compared with their PKR +/+,+/− littermates. In response to DSS colitis, the colonic epithelial cells of PKR −/− mice exhibited impaired activation of the unfolded protein response (UPR) signaling, including eIF2α phosphorylation, endoplasmic reticulum (ER) chaperone response, and ER‐associated degradation (ERAD) components, as well as antioxidative stress response. In addition, the phosphorylation of STAT3 and AKT, which are protective against epithelial cell death and colonic inflammation, was also impaired in the colonic epithelial cells of PKR −/− mice upon DSS colitis. Conclusions: These data demonstrate that PKR is a physiologically relevant transducer of inflammatory response signaling in colonic epithelial cells. PKR may promote the homeostasis and survival of intestinal epithelial cells (IECs) through eIF2α‐mediated UPR activation, as well as the activation of STAT3 and AKT pathways. In the absence of PKR, the survival and proliferation of IECs was impaired, thus exacerbating intestinal inflammation. (Inflamm Bowel Dis 2012;)