CCL20 Stimulates Proinflammatory Mediator Synthesis in Human Fibroblast-like Synoviocytes Through a MAP Kinase-dependent Process with Transcriptional and Posttranscriptional Control
Bibliographic record
Abstract
OBJECTIVE: To compare levels of the chemokine CCL20 and its receptor CCR6 in donor, osteoarthritic (OA), and rheumatoid arthritis (RA) synovium; and to determine the molecular mechanism of cellular activation induced by chemokine/receptor ligation in human fibroblast-like synoviocytes (FLS). METHODS: Synovia and isolated FLS from donor, OA, and RA joints were analyzed for CCL20 and CCR6 expression by RT-PCR and immunohistochemistry. The effect of CCL20 on cytokines and mediators of cartilage degradation was examined by PCR for mRNA expression levels and ELISA, and Western blotting for protein. CCL20-dependent transcriptional and posttranscriptional activation of target genes was monitored using reporter constructs and luciferase assays in transfected donor FLS. RESULTS: CCL20 and CCR6 proteins were abundantly expressed in RA synovial lining cells compared to donor or OA synovia as judged by immunohistochemistry. RT-PCR of synovial extracts confirmed the predominance of CCL20/CCR6 mRNA expression in RA synovium. CCL20 mRNA expression was low in donor FLS, but increased dramatically after stimulation with recombinant human (rh) interleukin 1ß (IL-1ß). rhCCL20 increased mRNA and protein expression of COX-2, IL-1ß, tumor necrosis factor-α, IL-6, and the matrix-destructive metalloprotease MMP-3 in donor FLS cultures. High constitutive levels of IL-6 were released from RA synovia; CCL20-induced expression of IL-6 occurred through an NSAID/COXIB-sensitive process. CCL20-induced expression of COX-2 was mediated by a PLCP1/PKCα/MEK1/2/ERK1/2-dependent pathway involving both transcriptional and posttranscriptional mechanisms. CONCLUSION: CCL20/CCR6 may play an important role in the pathogenesis of RA by assembling the molecular and cellular components orchestrating synovitis.
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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 | 0.001 |
| 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) | 0.003 | 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".