Tofacitinib downregulates JAK1 and JAK3 on human intestinal monocytes and macrophages without affecting dendritic cells phenotype or function
Background: Ulcerative colitis (UC) is an inflammatory disorder of the gastrointestinal tract. Although Tofacitinib, which inhibits the JAK1 and JAK3 signalling pathway, is approved to treat patients with UC, its specific mechanism of action remain elusive. Given the central role that conventional d...
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| Language: | English |
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Elsevier
2025-06-01
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| Series: | Journal of Translational Autoimmunity |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589909025000061 |
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| author | Elisa Arribas-Rodríguez Ángel De Prado Beatriz de Andrés Benito Velayos Jesús Barrio Alejandro Romero Francisco Javier García-Alonso Álvaro Martín-Muñoz José A. Garrote Eduardo Arranz Luis Fernández-Salazar David Bernardo |
| author_facet | Elisa Arribas-Rodríguez Ángel De Prado Beatriz de Andrés Benito Velayos Jesús Barrio Alejandro Romero Francisco Javier García-Alonso Álvaro Martín-Muñoz José A. Garrote Eduardo Arranz Luis Fernández-Salazar David Bernardo |
| author_sort | Elisa Arribas-Rodríguez |
| collection | DOAJ |
| description | Background: Ulcerative colitis (UC) is an inflammatory disorder of the gastrointestinal tract. Although Tofacitinib, which inhibits the JAK1 and JAK3 signalling pathway, is approved to treat patients with UC, its specific mechanism of action remain elusive. Given the central role that conventional dendritic cells (cDC) elicit in gut homeostasis, we hypothesised that Tofacitinib acts modulating cDC function in UC. Methods: Human biopsies were obtained from colon of controls, and patients with UC (active and quiescent). Lamina propria mononuclear cells (LPMC) were ex-vivo cultured in the presence/absence of Tofacitinib. The specific effect elicited over human intestinal cDC, monocytes and macrophages was assessed by flow cytometry. cDC were also enriched following Tofacitinib conditioning in order to assess its effect over naïve T-cells. Results: Several human intestinal cDC, monocyte and macrophage subsets can be found in the human colon, with these cells being more similar between controls and patients with qUC referred to patients with aUC. Following ex-vivo culture, Tofacitinib downregulated JAK1 expression on intestinal monocytes from patients with both active and quiescent UC. As for macrophages, JAK1 was decreased on patients with active UC while JAK was downregulated on macrophages from patients with quiescent disease. Tofacitinib did not modulate the phenotype or function of human intestinal cDC. Conclussion: Tofacitinib does not modulate the phenotype and function of human intestinal cDC in UC. On the contrary, it displays a differential capacity to modulate intestinal monocyte and macrophage phenotype. Future studies should address whether it also translates into a differential function of these cells. |
| format | Article |
| id | doaj-art-53dc50b7d1134472b44f2d617d834f12 |
| institution | Kabale University |
| issn | 2589-9090 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Translational Autoimmunity |
| spelling | doaj-art-53dc50b7d1134472b44f2d617d834f122025-01-27T04:22:07ZengElsevierJournal of Translational Autoimmunity2589-90902025-06-0110100271Tofacitinib downregulates JAK1 and JAK3 on human intestinal monocytes and macrophages without affecting dendritic cells phenotype or functionElisa Arribas-Rodríguez0Ángel De Prado1Beatriz de Andrés2Benito Velayos3Jesús Barrio4Alejandro Romero5Francisco Javier García-Alonso6Álvaro Martín-Muñoz7José A. Garrote8Eduardo Arranz9Luis Fernández-Salazar10David Bernardo11Mucosal Immunology Lab, Instituto Biomedicina y Genética Molecular (IBGM, Universidad de Valladolid-CSIC), Valladolid, SpainMucosal Immunology Lab, Instituto Biomedicina y Genética Molecular (IBGM, Universidad de Valladolid-CSIC), Valladolid, Spain; Servicio de Gastroenterología, Hospital Universitario Río Hortega, Valladolid, SpainServicio de Cirugía General, Hospital Clínico Universitario, Valladolid, SpainServicio de Gastroenterología, Hospital Clínico Universitario, Valladolid, SpainServicio de Gastroenterología, Hospital Universitario Río Hortega, Valladolid, SpainServicio de Cirugía General, Hospital Clínico Universitario, Valladolid, SpainServicio de Gastroenterología, Hospital Universitario Río Hortega, Valladolid, SpainCytometry Facility. Unidad de Excelencia Instituto Biomedicina y Genética Molecular (IBGM, Universidad de Valladolid-CSIC), Valladolid, SpainMucosal Immunology Lab, Instituto Biomedicina y Genética Molecular (IBGM, Universidad de Valladolid-CSIC), Valladolid, SpainMucosal Immunology Lab, Instituto Biomedicina y Genética Molecular (IBGM, Universidad de Valladolid-CSIC), Valladolid, SpainServicio de Gastroenterología, Hospital Clínico Universitario, Valladolid, SpainMucosal Immunology Lab, Instituto Biomedicina y Genética Molecular (IBGM, Universidad de Valladolid-CSIC), Valladolid, Spain; Centro de Investigaciones Biomédicas en Red de Enfermedades Infecciosas (CIBERINFEC), Madrid, Spain; Corresponding author. Mucosal Immunology Lab. Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid-CSIC. c/ Sanz y Forés 3. 47003. Valladolid, Spain.Background: Ulcerative colitis (UC) is an inflammatory disorder of the gastrointestinal tract. Although Tofacitinib, which inhibits the JAK1 and JAK3 signalling pathway, is approved to treat patients with UC, its specific mechanism of action remain elusive. Given the central role that conventional dendritic cells (cDC) elicit in gut homeostasis, we hypothesised that Tofacitinib acts modulating cDC function in UC. Methods: Human biopsies were obtained from colon of controls, and patients with UC (active and quiescent). Lamina propria mononuclear cells (LPMC) were ex-vivo cultured in the presence/absence of Tofacitinib. The specific effect elicited over human intestinal cDC, monocytes and macrophages was assessed by flow cytometry. cDC were also enriched following Tofacitinib conditioning in order to assess its effect over naïve T-cells. Results: Several human intestinal cDC, monocyte and macrophage subsets can be found in the human colon, with these cells being more similar between controls and patients with qUC referred to patients with aUC. Following ex-vivo culture, Tofacitinib downregulated JAK1 expression on intestinal monocytes from patients with both active and quiescent UC. As for macrophages, JAK1 was decreased on patients with active UC while JAK was downregulated on macrophages from patients with quiescent disease. Tofacitinib did not modulate the phenotype or function of human intestinal cDC. Conclussion: Tofacitinib does not modulate the phenotype and function of human intestinal cDC in UC. On the contrary, it displays a differential capacity to modulate intestinal monocyte and macrophage phenotype. Future studies should address whether it also translates into a differential function of these cells.http://www.sciencedirect.com/science/article/pii/S2589909025000061TofacitinibIntestineUlcerative colitisDendritic cellsMacrophages |
| spellingShingle | Elisa Arribas-Rodríguez Ángel De Prado Beatriz de Andrés Benito Velayos Jesús Barrio Alejandro Romero Francisco Javier García-Alonso Álvaro Martín-Muñoz José A. Garrote Eduardo Arranz Luis Fernández-Salazar David Bernardo Tofacitinib downregulates JAK1 and JAK3 on human intestinal monocytes and macrophages without affecting dendritic cells phenotype or function Journal of Translational Autoimmunity Tofacitinib Intestine Ulcerative colitis Dendritic cells Macrophages |
| title | Tofacitinib downregulates JAK1 and JAK3 on human intestinal monocytes and macrophages without affecting dendritic cells phenotype or function |
| title_full | Tofacitinib downregulates JAK1 and JAK3 on human intestinal monocytes and macrophages without affecting dendritic cells phenotype or function |
| title_fullStr | Tofacitinib downregulates JAK1 and JAK3 on human intestinal monocytes and macrophages without affecting dendritic cells phenotype or function |
| title_full_unstemmed | Tofacitinib downregulates JAK1 and JAK3 on human intestinal monocytes and macrophages without affecting dendritic cells phenotype or function |
| title_short | Tofacitinib downregulates JAK1 and JAK3 on human intestinal monocytes and macrophages without affecting dendritic cells phenotype or function |
| title_sort | tofacitinib downregulates jak1 and jak3 on human intestinal monocytes and macrophages without affecting dendritic cells phenotype or function |
| topic | Tofacitinib Intestine Ulcerative colitis Dendritic cells Macrophages |
| url | http://www.sciencedirect.com/science/article/pii/S2589909025000061 |
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