Role of Microglial-Derived Tumor Necrosis Factor in Mediating CD14 Transcription and Nuclear Factor κ B Activity in the Brain during Endotoxemia
Bibliographic record
Abstract
Systemic injection of the endotoxin lipopolysaccharide (LPS) upregulates the gene encoding CD14 early in the circumventricular organs (CVOs) and later in the brain parenchyma. The present study tested the hypothesis that the parenchymal production of the proinflammatory cytokine tumor necrosis factor α (TNF-α) by microglial cells is responsible for triggering CD14 transcription in an autocrine/paracrine loop-like manner. In a first set of experiments, Sprague Dawley rats were killed 1, 3, 6, and 12 hr after an intracerebroventricular administration of recombinant rat TNF-α or vehicle solution. Second, anti-rat TNF-α-neutralizing antibody or vehicle solution was administrated into the lateral ventricle 10 hr before an intraperitoneal injection of LPS. Central administration of the cytokine caused a strong induction of IκBα, TNF-α, and CD14 mRNA in parenchymal microglial cells. The hybridization signal for these transcripts was localized to the edge of the ventricles and the site of infusion. The time-related expression of each mRNA suggested that TNF-α has the ability to trigger its own production followed by the transcription of the LPS receptor; the signal for IκBα, TNF-α, and CD14 peaked at 1, 3, and 6 hr, respectively. The genes encoding TNF-α and mCD14 were also induced in the CVOs and within microglial cells across the brain parenchyma in response to intraperitoneal LPS administration. This induction in parenchymal cells of the brain was prevented in animals that received the anti-TNF-antisera intracerebroventricularly 10 hr before the systemic treatment with the endotoxin. The present data provide the evidence that microglial-derived TNF-α is responsible for the production of the LPS receptor CD14 during endotoxemia. This autocrine/paracrine stimulatory loop may be of great importance in controlling the inflammatory events that take place in the CNS during innate immune response as well as under pathological conditions.
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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".