title: PKR protects colonic epithelium against colitis through the unfolded protein response and prosurvival signaling.
abstract: 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.
authors.affiliation: Del E. Webb Neuroscience, Aging and Stem Cell Research Center, Sanford Burnham Medical Research Institute, La Jolla, California 92037-1062, USA.
authors.forename: Stewart Siyan
authors.initials: SS
authors.lastname: Cao
authors.forename: Benbo
authors.initials: B
authors.lastname: Song
authors.forename: Randal J
authors.initials: RJ
authors.lastname: Kaufman
mesh_terms: D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D003092:Colitis / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D003106:Colon / Q000378:metabolism / Q000473:pathology*; D016264:Dextran Sulfate / Q000633:toxicity; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism / Q000473:pathology*; D005260:Female; D007124:Immunoenzyme Techniques; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D056811:Unfolded Protein Response / Q000502:physiology*; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D016264:Dextran Sulfate; D051057:Proto-Oncogene Proteins c-akt; D019892:eIF-2 Kinase