<scp>TRPV4</scp> mediates <scp>IL</scp> ‐1‐induced Ca <sup>2+</sup> signaling, <scp>ERK</scp> activation and <scp>MMP</scp> expression
Bibliographic record
Abstract
Abstract Ca 2+ permeation through TRPV4 in fibroblasts is associated with pathological matrix degradation. In human gingival fibroblasts, IL‐1β binding to its signaling receptor (IL‐1R1) induces activation of extracellular regulated kinase (ERK) and MMP1 expression, processes that require Ca 2+ flux across the plasma membrane. It is not known how IL‐1R1, which does not conduct Ca 2+ , generates Ca 2+ signals in response to IL‐1. We examined whether TRPV4 mediates the Ca 2+ fluxes required for ERK signaling in IL‐1 stimulated gingival fibroblasts. TRPV4 was immunostained in fibroblasts of human gingival connective tissue and in focal adhesions of cultured mouse gingival fibroblasts. Human gingival fibroblasts treated with IL‐1β showed no change of TRPV4 expression but there was increased MMP1 expression. In mouse, gingival fibroblasts expressing TRPV4, IL‐1 strongly increased [Ca 2+ ] i . Pre‐incubation of cells with IL‐1 Receptor Antagonist blocked Ca 2+ entry induced by IL‐1 or the TRPV4 agonist GSK101. Knockout of TRPV4 or expression of a non‐Ca 2+ ‐conducting TRPV4 pore‐mutant or pre‐incubation with the TRPV4 inhibitor RN1734, blocked IL‐1‐induced Ca 2+ transients and expression of the mouse interstitial collagenase, MMP13. Treatment of mouse gingival fibroblasts with GSK101 phenocopied Ca 2+ and ERK responses induced by IL‐1; these responses were absent in TRPV4‐null cells or cells expressing a non‐conducting TRPV4 pore‐mutant. Immunostained IL‐1R1 localized with TRPV4 in adhesions within cell extensions. While TRPV4 immunoprecipitates analyzed by mass spectrometry showed no association with IL‐1R1, TRPV4 associated with Src‐related proteins and Src co‐immunoprecipitated with TRPV4. Src inhibition reduced IL‐1‐induced Ca 2+ responses. The functional linkage of TRPV4 with IL‐1R1 expands its repertoire of innate immune signaling processes by mediating IL‐1‐driven Ca 2+ responses that drive matrix remodeling in fibroblasts. Thus, inhibiting TRPV4 activity may provide a new pharmacological approach for blunting matrix degradation in inflammatory diseases.
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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 | 0.001 |
| 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 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".