Regulation of intestinal epithelial apoptosis by protease‐activated receptor 2 involves EGFR‐transactivation and is associated with Mcl‐1 upregualtion (151.1)
Bibliographic record
Abstract
Colonic biopsies from inflamed colon have higher levels of epithelial apoptosis than biopsies from healthy individuals. Therapies that inhibit intestinal epithelial apoptosis may decrease the inflammation observed in inflammatory bowel disease. We previously showed that signaling by PAR2, a GPCR activated by serine proteases, delayed IFN‐γ & TNF‐α‐induced apoptosis in colonic epithelial (HT‐29) cells. The observed decrease in the cleavage of caspase‐8, 9, 3 and PARP following the activation of PAR2 by 2‐furoyl‐LIGRLO (2fLI) was shown to be dependent on the activities of PI3K and ERK1/2. In this study we found that selective inhibition of EGFR with AG1478 blocked the phosphorylation of PI3K and ERK1/2. Pre‐treatment with AG1478 prior to the addition of IFN‐γ & TNF‐α also blocked 2fLI‐induced intestinal epithelial survival, as determined by PARP cleavage. Modulation of BCL‐2 family members was then investigated due to their known function in regulating mitochondrial permeability and apoptosis. Protein expression of pro‐apoptotic BAK, BAX and BIM were not altered by either cytokine or 2fLI treatment. Likewise, no change in expression of anti‐apoptotic BCL‐XL was observed. Treatment with 2fLI stimulated phosphorylation and inactivation of the apoptotic BH3‐only protein, BAD. Knockdown of BAD with siRNA, however, did not alter 2fLI‐stimulated intestinal survival. Finally, 2fLI stimulated a rapid increase in anti‐apoptotic MCL‐1 expression. PAR2 signaling reduces epithelial apoptosis in response to inflammatory cytokines via EGFR transactivation and possibly by regulation of MCL‐1 expression. Our findings may represent a mechanism whereby proteases facilitate epithelial cell survival and colonic healing after inflammation. Grant Funding Source : Supported by the Crohn’s and Colitis Foundation of Canada
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".