| Title: |
Resistance to apoptosis in complicated Crohn's disease: Relevance in ileal fibrosis |
| Authors: |
Seco Cervera, Marta; Ortiz Masiá, María Dolores; Macías Ceja, Dulce Carolina; Coll, Sandra; Gisbert Ferrándiz, Laura; Cosín Roger, Jesús; Bauset Pastor, Cristina; Ortega Albiach, Carme Maria; Heras-Moran,Begoña; Esplugues Mota, Juan Vicente; Calatayud Romero, Sara; Barrachina Sancho, María Dolores |
| Source: |
Seco Cervera, Marta Ortiz Masiá, María Dolores Macías Ceja, Dulce Carolina Coll, Sandra Gisbert Ferrándiz, Laura Cosín Roger, Jesús Bauset Pastor, Cristina Ortega Albiach, Carme Maria Heras-Moran,Begoña Esplugues Mota, Juan Vicente Calatayud Romero, Sara Barrachina Sancho, María Dolores 2024 Resistance to apoptosis in complicated Crohn's disease: Relevance in ileal fibrosis Biochimica et Biophysica Acta-Molecular Basis of Disease 1870 2 Art. 166966 |
| Publication Year: |
2025 |
| Collection: |
Universitat de València: Roderic - Repositorio de contenido libre |
| Subject Terms: |
aparell digestiu malalties; bioquímica |
| Description: |
Background and aims. The stiffening of the extracellular matrix, and changes in its cellular and molecular composition, have been reported in the pathogenesis of fibrosis. We analyze the mechanisms that perpetuate ileal fibrosis in surgical resections of complicated Crohn's disease patients. Methods. Ileal resections were obtained from affected and non-affected tissue of stenotic or penetrating Crohn's disease behavior. Ilea from non-IBD patients were used as control tissue. All samples underwent RNA sequencing. Human small intestinal fibroblasts were treated for 48 h with IL-1β, TFGβ1, PDGFB or TNF-α. Resistance to apoptosis was analysed by RT-PCR, western blot and immunohistochemistry in ileal tissue and by RT-PCR and FACS in cultured cells. Results. Growth factor-driven signaling pathways and increased RAS GTPase activity were up-regulated in affected ilea in which we found expression of both the antiapoptotic molecule MCL1 and the transcription factor ETS1 in submucosal fibroblasts, and a senescence-associated secretory phenotype. In cultured intestinal fibroblasts, PDGFB induced an ETS1-mediated resistance to apoptosis that was associated with the induction of both of TGFB1 and IL1B, a cytokine that replicated the expression of SASP detected in ileal tissue. ETS1 drove fibroblast polarization between inflammatory and fibrogenic phenotypes in IL1β-treated cells. Conclusions. Our data show resistance to apoptosis in complicated ileal CD, and demonstrate that PDGFB induce an ETS1-mediated resistance to apoptosis associated with an inflammatory and fibrogenic pattern of expression in intestinal fibroblasts. Results point to PDGFRB, IL1R1 or MCL1 as potential targets against ileal fibrosis. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
Biochimica et Biophysica Acta-Molecular Basis of Disease, 2024, vol. 1870, num. 2, p. Art. 166966; https://hdl.handle.net/10550/114152; 163411 |
| DOI: |
10.1016/j.bbadis.2023.166966 |
| Availability: |
https://hdl.handle.net/10550/114152; https://doi.org/10.1016/j.bbadis.2023.166966 |
| Rights: |
open access |
| Accession Number: |
edsbas.525FFD0A |
| Database: |
BASE |