CpG motifs in bacterial DNA evokes peroxynitrite signaling in human neutrophils
Bibliographic record
Abstract
Bacterial DNA is emerging as an important regulator of functions of human neutrophil granulocytes. Bacterial DNA contains short sequences of nonmethylated CpG dinucleotides (CpG‐DNA) that are recognized by TLR‐9. Evidence suggests that peroxynitrite (ONOO‐) may function as an intracellular signal for cytokine production in neutrophils. We investigated whether CpG‐DNA evokes ONOO‐ signaling in neutrophils. High purity (>99.9%) human neutrophils express TLR‐9 and respond to CpG‐DNA (0.2‐10 μg/ml), but not to thymus DNA, with secretion of IL‐8 and, to a considerably lesser extent, IL‐6. Methylation of cytosines in CpG‐DNA resulted in a complete loss of activity. CpG‐DNA‐induced IL‐8 mRNA expression and IL‐8 release were blocked by inhibitors of endosomal acidification and L‐NAME. CpG‐DNA evoked concomitant formation of superoxide and NO, coinciding with ONOO‐ formation (assessed by dihydrorhodamine oxidation and nitrotyrosine formation). RT‐PCR amplified endothelial NO synthase in neutrophils cultured with or without CpG‐DNA. CpG‐DNA evoked rapid mobilization of NF‐kB and c‐Fos to the nucleus that were attenuated by L‐NAME parallel with inhibition of IL‐8 mRNA expression. Pharmacological blockade of NF‐kB activation attenuated ~75% of CpG‐DNA‐evoked IL‐8 release. These results provide evidence that bacterial DNA and unmethylated CpG motifs in particular activate ONOO‐ signaling in neutrophils, underlying IL‐8 gene and protein expression through activation of NF‐kB and c‐Fos. (Supported by CIHR MOP‐64283).
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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) | 0.000 | 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) | 0.001 | 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 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".