Abstract 2: Elucidation of the Mechanism of Apolipoprotein(a)/Lipoprotein(a)-Induced Interleukin 8 Gene Expression: Insight into Potential Receptors and Signaling Pathways and the Role of Oxidized Phospholipids
Bibliographic record
Abstract
Elevated plasma Lipoprotein(a) (Lp(a)) levels are a risk factor for a variety of atherosclerotic disorders, although the exact role(s) of Lp(a) in atherogenesis remains poorly understood. It is clear, however, that the unique pathogenic effects attributed to Lp(a) are mediated by its apolipoprotein(a) moiety. Over the past decade, a growing body of evidence suggests that the harmful effects of apo(a) involve stimulation of inflammatory responses such as monocyte chemotaxis. It was previously reported that Lp(a), through apo(a), induces IL-8 gene expression by macrophages. The kringle V domain of apo(a) was implicated in this effect, along with oxidized phospholipids potentially present in this domain. In the current study, we found that a recombinant apo(a) species containing 17 kringle-IV domians (17K) elicited a dose-dependant increase in IL-8 mRNA abundance and protein secretion in THP-1 macrophages. This effect was significantly reduced by mutation of the strong lysine binding site (sLBS) in kringle IV type 10, but not by treatment with lysine analogue ε-ACA. Notably, this mutation eliminates the EO6-reactive oxidized phsopholipid in apo(a). Removal of kringle V did not reduce the ability of apo(a) to enhance IL-8 expression. Therefore, to examine the potential role of the modification of apo(a) by oxidized phospholipids, we used an siRNA knockdown approach to screen candidate receptors. We found that CD36 and TLR2, but not TLR4, are required for apo(a)-induced IL-8 expression. Specific MAPK pathway inhibitors were used to investigate the mechanism of IL-8 induction by apo(a): inhibitors of JNK and ERK1/2 abolished the effect of apo(a) whereas an inhibitor of p38 had no effect. Accordingly, apo(a) also stimulated an increase in JNK phosphorylation. To assess the role of downstream transcription factors, luciferase reporter gene experiments were conducted using the IL-8 promoter. Apo(a) induced expression of this reporter construct, as expected, and this induction was eliminated by mutation of known binding sites for NFκB or AP-1. Our results provide tantalizing mechanistic links between apo(a) lysine binding function, oxidative modification, and stimulation of intracellular signaling pathways through inflammation-linked receptors.
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 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".