NADPH Oxidase–Derived Superoxide Destabilizes Lipopolysaccharide-Induced Interleukin 8 mRNA Via p38, Extracellular Signal–Regulated Kinase Mitogen-Activated Protein Kinase, and the Destabilizing Factor Tristetraprolin
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Bibliographic record
Abstract
Expression of inflammatory cytokines is regulated by transcriptional and posttranscriptional mechanisms. We previously showed that NADPH oxidase-derived superoxide induces inflammatory mediators in response to tumor necrosis factor α (TNF-α) and lipopolysaccharide (LPS). In this study, we examined the role of endothelial NADPH oxidase in the regulation of mRNA stability of three inflammatory mediators: interleukin (IL) 8, IL-6, and intercellular adhesion molecule 1 (ICAM-1). Tumor necrosis factor α increased mRNA stability of ICAM-1, IL-8, and IL-6 by a p38 mitogen-activated protein kinase (MAPK)-dependent mechanism, but this did not involve NADPH oxidase. Surprisingly, whereas LPS treatment alone did not alter stability of these molecules, the antioxidant N-acetyl-L-cysteine; the flavine inhibitor diphenylene iodonium; short interfering RNA against Nox2, Nox4; and the p22(phox) subunit of NADPH oxidase all enhanced IL-8 mRNA stability in LPS-treated cells, indicating that LPS induced destabilization through NADPH oxidase. This occurred by a mechanism that involved extracellular signal-regulated kinase 1/2, p38 MAPK, and the mRNA-destabilizing factor tristetraprolin. On the other hand, N-acetyl-L-cysteine decreased mRNA stability of ICAM-1 and IL-6 in LPS-treated cells and IL-6 and ICAM-1 in TNF-α-treated cells. In conclusion, NADPH oxidase contributes to destabilization of IL-8 mRNA stability and propose a model for the complex underlying mechanism, which is dependent upon agonist (LPS vs. TNF-α) and target molecule (IL-8 vs. IL-6 and ICAM-1) and involves tristetraprolin, p38, and extracellular signal-regulated kinase 1/2 MAPK.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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 it