{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T08:01:22Z","timestamp":1785225682014,"version":"3.55.0"},"reference-count":59,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T00:00:00Z","timestamp":1785196800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T00:00:00Z","timestamp":1785196800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01DK114457"],"award-info":[{"award-number":["R01DK114457"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001602","name":"Science Foundation Ireland","doi-asserted-by":"publisher","award":["21\/PATH\u2010S\/9621"],"award-info":[{"award-number":["21\/PATH\u2010S\/9621"]}],"id":[{"id":"10.13039\/501100001602","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001596","name":"Irish Research Council for Science, Engineering and Technology","doi-asserted-by":"publisher","award":["21\/PATH\u2010S\/9621"],"award-info":[{"award-number":["21\/PATH\u2010S\/9621"]}],"id":[{"id":"10.13039\/501100001596","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001596","name":"Irish Research Council for Science, Engineering and Technology","doi-asserted-by":"publisher","award":["GOIPD\/2025\/1089"],"award-info":[{"award-number":["GOIPD\/2025\/1089"]}],"id":[{"id":"10.13039\/501100001596","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001596","name":"Irish Research Council for Science, Engineering and Technology","doi-asserted-by":"publisher","award":["GOIPD\/2023\/1118"],"award-info":[{"award-number":["GOIPD\/2023\/1118"]}],"id":[{"id":"10.13039\/501100001596","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>\n                      Fibroblasts have emerged as inflammatory entities in ulcerative colitis (UC) and eosinophilic oesophagitis, positioning these cells as attractive therapeutic targets. Previous studies have shown that hydroxylase inhibitors elicit anti\u2010inflammatory responses, but their effects on fibroblasts during inflammation remain unknown. Here we test the effects of hydroxylase inhibitors on TNFSF14\/LIGHT\u2010driven inflammation in intestinal and oesophageal fibroblasts. Human endoscopic biopsies were obtained from paired inflamed or non\u2010inflamed areas of active UC patients. Primary human colonic and oesophageal fibroblasts from healthy donors were pre\u2010treated with hydroxylase inhibitors and\/or treated with LIGHT. Flow cytometry, qRT\u2010PCR, enzyme\u2010linked immunosorbent assays, immunoblotting, immunofluorescence and RNAseq were used. LIGHT induced inflammatory responses in intestinal fibroblasts predominantly via lymphotoxin \u03b2 receptor (LT\u03b2R), which was more highly expressed than herpes virus entry mediator in UC biopsies and colonic fibroblasts. A comparative analysis of the response to LIGHT between colonic and oesophageal fibroblasts revealed unique transcriptional profiles and a shared inflammatory gene programme. Pretreatment with hydroxylase inhibitors had a selective inhibitory effect on the expression of several LIGHT\u2010mediated inflammatory factors in colonic and oesophageal fibroblasts. Mechanistic studies revealed differential molecular targets as LIGHT\u2010driven non\u2010canonical nuclear factor\u2010\u03baB activity was targeted by hydroxylase inhibitors in oesophageal but unaffected in colonic fibroblasts. While dimethyloxalylglycine (DMOG) abrogated LIGHT\u2010induced p38 phosphorylation in colonic fibroblasts, p38 inhibitors did not phenocopy the anti\u2010inflammatory effects of DMOG. In summary, we established a previously unrecognised LIGHT\/LT\u03b2R\u2010driven inflammatory response in intestinal fibroblasts and characterised differential effects and pathways for LIGHT signalling in intestinal and oesophageal fibroblasts. We identified therapeutic effects of hydroxylase inhibitors via targeting of distinct pathways in these cells.\n                      <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                        <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp70726-gra-0001-m.png\">\n                          <jats:alt-text>image<\/jats:alt-text>\n                        <\/jats:graphic>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>LIGHT induces partially conserved inflammatory responses in colonic and oesophageal fibroblasts.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Hydroxylase inhibitors selectively diminish LIGHT\u2010mediated inflammation in both types of fibroblasts.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Dimethyloxalylglycine reduces accumulation of the non\u2010canonical nuclear factor\u2010\u03baB member p52 in oesophageal fibroblasts.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>The mechanism whereby hydroxylase inhibitors reduce LIGHT\u2010mediated inflammation in colonic fibroblasts remains to be elucidated.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  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