A20 NOVEL REGULATION OF A PAR2-MEDIATED CELLULAR MIGRATION PROGRAM BY PRO-INFLAMMATORY CYTOKINES
Notice bibliographique
Résumé
Mucosal healing is the gold standard for IBD therapy. However, the mechanisms that determine mucosal healing are complex and need to be better understood to explain why many patients fail to achieve this key goal of therapy. The inflammatory environment is characterized by the presence of several serine proteases that signal through the protease-activated receptors (PARs). PAR2 is ubiquitously expressed in the epithelial cells of the intestinal mucosa and activation serves a protective role consistent with host defence and repair. While our preliminary findings indicate that activation of PAR2 enhances wound closure, we do not know the cellular mechanisms that underlie this response. We hypothesize that activation of PAR2 induces a cellular migration program in intestinal epithelial cells that enhances mucosal healing in the inflammatory milieu. Circular wounds were introduced in T84 colonic epithelial cells. Wounded monolayers were treated with the PAR2 activating peptide, 2-furoyl-LIGRLO (2fLI, 5 µM), or the control reverse-sequence peptide, 2-furoyl-OLRGIL (2fO, 5 µM), and live cell imaging was utilized to record wound closure over a 24 hr period. In other experiments, a cytokine cocktail consisting of IFNγ (10 ng/mL) and TNFα (10 ng/mL), alone or in combination with 2fLI, was applied to wounded monolayers and wound closure assessed. Intracellular effects of PAR2 activation and cytokine treatment were evaluated by measuring phosphorylation of key canonical signaling proteins using the MSD multi-plex ELISA array system. EdU staining, with or without Mitomycin C (MMC), an inhibitor of proliferation, was used to determine the effect of cellular proliferation on wound closure. PAR2 activation by 2fLI promoted wound closure in a concentration-dependent manner compared to 2fO controls at the 12 and 24 hr timepoints. Interestingly, co-stimulation with 2fLI and the cytokine cocktail resulted in an enhanced wound closure response at the 12 and 24 hr timepoints that was significantly greater than individual treatments (p<0.001). Co-stimulation activated the downstream intracellular targets ERK1/2 and JNK compared to 2fO (p<0.001), but this activation was not greater than stimulation with 2fLI or cocktail alone, suggesting that MAP kinase activation was not responsible for the enhanced effect. MMC pre-treatment partially reduced wound closure caused by co-stimulation with 2fLI/IFNγ/TNFα, indicating that the enhanced wound healing effect was due in part to increased proliferation. These data suggest that both PAR2 activation and cytokine treatment promote wound closure in vitro through both enhanced cell migration and proliferation. The enhanced wound healing response to PAR2 activation in the presence of pro-inflammatory cytokines suggests that the inflammatory milieu is necessary to initiate a proper wound healing response. CIHR
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,005 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».