Disparate Regulation of LPS-Induced MAPK Signaling and IL-12p40 Expression Between Different Myeloid Cell Types with and without HIV Infection
Bibliographic record
Abstract
Studies from our laboratory and those of others have implicated lipopolysaccharide (LPS)-induced MAPK signaling as an important pathway in the regulation of cytokine expression. In this article, the regulation of IL-12 expression in two different human myeloid cell populations was evaluated. In primary monocytes, the inhibition of p38 enhanced IL-12 production, whereas it downregulated IL-12 production in THP-1 cells. The role of MAPK signaling in transcription factor binding to the IL-12p40 promoter was subsequently determined. In primary monocytes, ERK and p38 inhibition increased binding of AP-1 and Sp1, respectively, to the IL-12p40 promoter, while JNK inhibition increased NF-kappaB, AP-1, and Sp1 binding. In THP-1 cells, p38, ERK, and JNK inhibition increased NF-kappaB and Sp1 binding to the IL-12p40 promoter, while inhibiting AP-1 binding. In monocytes, mutations in the NF-kappaB, AP-1, Sp1, or Ets-2 binding sites resulted in complete inhibition of LPS-stimulated IL-12p40 promoter activity using a luciferase-based assay. In contrast, promoter activity was abrogated in THP-1 cells only when the Sp1 or Ets-2 binding sites were mutated. Transcription factor binding to the IL-12p40 promoter following in-vitro HIV infection demonstrated several differences between monocytes and THP-1 cells. Infection with HIV produced an increase in NF-kappaB, AP-1, and Sp1 binding in primary monocytes. In contrast, binding of Ets-2 was dramatically impaired following HIV infection of monocytes, but was unaffected in THP-1 cells. These data clearly show that although LPS induces IL-12p40 expression in primary monocytes and THP-1 cells, the signaling pathways involved and the effect of HIV infection differ and can have disparate effects in these two cell types.
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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".