Interleukin 17 (IL-17) induces collagenase-3 production in human osteoarthritic chondrocytes via AP-1 dependent activation: differential activation of AP-1 members by IL-17 and IL-1beta.
Bibliographic record
Abstract
OBJECTIVE: In osteoarthritic (OA) synovial fluid, many proinflammatory cytokines coexist and stimulate chondrocytes. As interleukin 17 (IL-17) is a catabolic cytokine, we explored its effects on collagenase-3 production. In a comparative manner we identified IL-17 and IL-1beta induced transcription factors mediating upregulation of this enzyme's production. METHODS: Collagenase-3 levels were determined by ELISA. Transfection experiments of human OA chondrocytes were performed, with the plasmids -1599CAT and -133CAT consisting of 1.6 kb and the first proximal 133 bp containing polyomavirus enhancer A-3 (PEA-3), activating protein-1 (AP-1), and TATA box of the human collagenase-3 promoter, respectively. Electrophoretic mobility shift assays were done with the AP-1 and PEA-3 oligonucleotides derived from the human collagenase-3 promoter sequence. Supershift assays were carried out with the specific antibodies against the Jun and Fos proteins. RESULTS: IL-17 induced collagenase-3 expression and synthesis, with an EC50 at 10 ng/ml. Transfection experiments with wild-type -1599CAT and -133CAT and their mutated AP-1 or PEA-3 derivatives revealed that the AP-1 site was essential for basal and proinflammatory cytokine induced collagenase-3 promoter activity, whereas the PEA-3 motif exerted a cooperative effect. Of note, in OA chondrocytes, IL-17 and IL-1beta induced collagenase-3 production through AP-1 occurred with differential protein complexes: IL-17 stimulation resulted in FosB activation, while IL-1beta stimulated c-Fos. Data showed a strong activation of JunB only in cells showing a higher collagenase-3 basal level and low cytokine (IL-17 and IL-1beta) inducibility, suggesting this transcription factor protein acts as a negative regulator. CONCLUSION: We demonstrated that IL-17 and IL-1beta induced collagenase-3 production in OA chondrocytes mainly through AP-1 mediated transcriptional activity but with differential protein complexes, suggesting that some AP-1 proteins play a pivotal role in the different cytokine responses in terms of collagenase-3 production. Our data might suggest that JunB protein plays a rate-limiting step in cytokine induced collagenase-3 production in OA chondrocytes.
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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) | 0.001 | 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) | 0.002 | 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".