Disruption of Epithelial Barrier Integrity via Altered GILZ/c-Rel/RACK1 Signaling in Inflammatory Bowel Disease
Bibliographic record
Abstract
BACKGROUND AND AIMS: Given the role of Receptor for Activated C Kinase 1 (RACK1) in both immune cell activation and in the maintenance of the intestinal epithelial barrier integrity, we investigated whether it was involved in inflammatory bowel disease (IBD). METHODS: RACK1 expression was analyzed in intestinal mucosal samples of healthy and IBD patients, in mice with chemically induced colitis, and in diseased in vitro 2D and 3D coculture models by luciferase assay, reverse transcription-quantitative PCR, Western blotting, immunofluorescence, and immunohistochemistry. Based on our finding that glucocorticoid-induced leucine zipper (GILZ or tsc22d3) positively correlates with RACK1 expression in IBD patients, GILZ knockout mice and cell silencing experiments were performed. RESULTS: RACK1 was significantly decreased in IBD, especially in ulcerative colitis. This was associated with an NF-κB/c-Rel-related mechanism, correlating with decreased GILZ protein expression. GILZ depletion confirmed a decrease in RACK1 expression, which favored SRC activation and led to a significant reduction in E-cadherin, resulting in impaired epithelial barrier integrity. Finally, our data highlighted that this novel mechanism could be considered to develop new therapies since dexamethasone, the first line of treatment in IBD, restored RACK1 expression through the glucocorticoid receptor in a c-Rel/GILZ-independent manner. CONCLUSIONS: We provide the first evidence that an alteration of RACK1/SRC/E-cadherin regulatory mechanism, correlating with decreased GILZ protein expression, is involved in epithelial barrier disruption. The clinical relevance is based on the fact that this mechanism involving GILZ/c-Rel-related RACK1 expression could be considered to improve IBD therapies, particularly in patients with low or no response to glucocorticoid treatment.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 teacher head, 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".