Endoplasmic reticulum stress modulates TLR responses in intestinal epithelial cells
Bibliographic record
Abstract
Endoplasmic reticulum (ER) stress induces a coordinated transcriptional and translational program called the unfolded protein response (UPR). Dysregulated ER stress is implicated in a number of diseases, including IBD. We previously reported that ATP and H2O2, two important signals of cellular injury, modulate flagellin/TLR5 responses in Caco-2 cells by increasing IL-8 and decreasing CCL20 expression. We hypothesized that ER stress, acting as an endogenous cellular danger signal, would have a similar effect. Caco-2 cells were pretreated with thapsigargin (Tg) 1 μM overnight, or tunicamycin (Tm) 20 μM for 6h, to induce the ER stress. Cells were then stimulated with flagellin 100 ng/ml with or without ATP or H2O2. Expression of UPR effectors (CHOP, spliced XBP1, and GRP78) and chemokine production were measured by QPCR and ELISA, respectively. Activation of p38 and ERK1/2 MAP kinases were measured by Western blot using phospho-specific antibodies. Tg and Tm both induced a robust UPR, athough Tg was more active than Tm. Pretreatment of Caco-2 cells with either Tg or Tm significantly enhanced flagellin-induced IL-8 production while inhibiting CCL20 production. ATP and H2O2 did not enhance the effects of ER stressors on chemokine production, but H2O2 alone induced a small but significant upregulation of CHOP. While CHOP is generally considered a transcriptional inhibitor, it is reported to activate IL-8 transcription through a unique promoter element. Thus it is possible that H2O2 and ER stress share a common pathway to increase IL-8 transcription in IECs. As has been reported for other TLR agonists, flagellin inhibited CHOP expression that was induced by Tg or Tm, but did not affect XBP1 splicing or GRP78 expression. Finally, Tg inhibited flagellininduced ERK and p38 phosphorylation, suggesting that the augmentation of IL-8 expression is independent of these MAP kinases. Given that a dysregulated UPR is associated with UC and murine colitis, these data suggest a potential mechanism whereby ER stress in IECs may affect their function as inflammatory cells, leading to colitis.
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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) | 0.001 | 0.001 |
| 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 | 0.001 |
| 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".