Yi He, Bennie Van Heeswijk, Adriana M C Mus, Nadine Davelaar, Radjesh Bisoendial, Erik Lubberts
{"title":"活性维生素D通过调节人Th17活性在银屑病滑膜成纤维细胞活化模型中作为抗tnf α治疗的辅助剂。","authors":"Yi He, Bennie Van Heeswijk, Adriana M C Mus, Nadine Davelaar, Radjesh Bisoendial, Erik Lubberts","doi":"10.1136/rmdopen-2025-005547","DOIUrl":null,"url":null,"abstract":"<p><strong>Objectives: </strong>Psoriatic arthritis (PsA) is an IL-23/IL-17/TNF-driven inflammatory arthritis, commonly accompanied by vitamin D deficiency. Here, we investigate the interaction between PsA synovial fibroblasts (SFs) and human memory CCR6+Th17 (hmemCCR6+Th17) cells and evaluate the therapeutic effects of TNFα and/or IL-17A inhibitors, and the adjunctive therapy potential of 1,25-dihydroxyvitamin D3 (1,25(OH)<sub>2</sub>D<sub>3</sub>).</p><p><strong>Methods: </strong>SF derived from PsA biopsies were co-cultured with hmemCCR6+Th17 cells to construct a PsA SF activation model. SF phenotypes were analysed by flow cytometry. Treatments included adalimumab (anti-TNFα), secukinumab (anti-IL-17A), and/or 1,25(OH)<sub>2</sub>D<sub>3</sub>, applied alone or in combination. A transwell system was used to assess treatment effects on SF and hmemCCR6+Th17 cells. Cytokines and matrix metalloproteinases (MMPs) were quantified by ELISA.</p><p><strong>Results: </strong>PsA SF were composed of heterogeneous subpopulations and constructed a pro-inflammatory feedback loop with hmemCCR6+Th17 cells. Anti-TNFα and/or anti-IL-17A significantly suppressed proinflammatory cytokines and tissue-destructive mediators in the PsA SF activation model, but showed limited effect on IL-22 and IFNγ. Adding 1,25(OH)<sub>2</sub>D<sub>3</sub> to anti-TNFα treatment effectively overcame the limitations of single anti-TNFα in suppressing Th17 cytokines, while significantly enhancing the inhibition of IL-6, IL-8 and MMPs. In addition, 1,25(OH)<sub>2</sub>D<sub>3</sub> promoted the production of IL-10.</p><p><strong>Conclusions: </strong>TNFα or IL-17A inhibition alone does not completely inhibit the proinflammatory loop between hmemCCR6+Th17 cells and PsA SF, although the combination shows additive effect on suppressing proinflammatory and tissue-destructive mediators. Importantly, 1,25(OH)<sub>2</sub>D<sub>3</sub> plays a complementary role in the treatment of this proinflammatory loop alongside anti-TNFα therapy and significantly induces IL-10. Clinical PsA studies are needed to explore the additional therapeutic potential of this combination.</p>","PeriodicalId":21396,"journal":{"name":"RMD Open","volume":"11 3","pages":""},"PeriodicalIF":4.7000,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12458773/pdf/","citationCount":"0","resultStr":"{\"title\":\"Active vitamin D acts in vitro as an adjuvant to anti-TNFα treatment in a psoriatic synovial fibroblast activation model by modulating human Th17 activity.\",\"authors\":\"Yi He, Bennie Van Heeswijk, Adriana M C Mus, Nadine Davelaar, Radjesh Bisoendial, Erik Lubberts\",\"doi\":\"10.1136/rmdopen-2025-005547\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objectives: </strong>Psoriatic arthritis (PsA) is an IL-23/IL-17/TNF-driven inflammatory arthritis, commonly accompanied by vitamin D deficiency. Here, we investigate the interaction between PsA synovial fibroblasts (SFs) and human memory CCR6+Th17 (hmemCCR6+Th17) cells and evaluate the therapeutic effects of TNFα and/or IL-17A inhibitors, and the adjunctive therapy potential of 1,25-dihydroxyvitamin D3 (1,25(OH)<sub>2</sub>D<sub>3</sub>).</p><p><strong>Methods: </strong>SF derived from PsA biopsies were co-cultured with hmemCCR6+Th17 cells to construct a PsA SF activation model. SF phenotypes were analysed by flow cytometry. Treatments included adalimumab (anti-TNFα), secukinumab (anti-IL-17A), and/or 1,25(OH)<sub>2</sub>D<sub>3</sub>, applied alone or in combination. A transwell system was used to assess treatment effects on SF and hmemCCR6+Th17 cells. Cytokines and matrix metalloproteinases (MMPs) were quantified by ELISA.</p><p><strong>Results: </strong>PsA SF were composed of heterogeneous subpopulations and constructed a pro-inflammatory feedback loop with hmemCCR6+Th17 cells. Anti-TNFα and/or anti-IL-17A significantly suppressed proinflammatory cytokines and tissue-destructive mediators in the PsA SF activation model, but showed limited effect on IL-22 and IFNγ. Adding 1,25(OH)<sub>2</sub>D<sub>3</sub> to anti-TNFα treatment effectively overcame the limitations of single anti-TNFα in suppressing Th17 cytokines, while significantly enhancing the inhibition of IL-6, IL-8 and MMPs. In addition, 1,25(OH)<sub>2</sub>D<sub>3</sub> promoted the production of IL-10.</p><p><strong>Conclusions: </strong>TNFα or IL-17A inhibition alone does not completely inhibit the proinflammatory loop between hmemCCR6+Th17 cells and PsA SF, although the combination shows additive effect on suppressing proinflammatory and tissue-destructive mediators. Importantly, 1,25(OH)<sub>2</sub>D<sub>3</sub> plays a complementary role in the treatment of this proinflammatory loop alongside anti-TNFα therapy and significantly induces IL-10. Clinical PsA studies are needed to explore the additional therapeutic potential of this combination.</p>\",\"PeriodicalId\":21396,\"journal\":{\"name\":\"RMD Open\",\"volume\":\"11 3\",\"pages\":\"\"},\"PeriodicalIF\":4.7000,\"publicationDate\":\"2025-09-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12458773/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"RMD Open\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1136/rmdopen-2025-005547\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"RHEUMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"RMD Open","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1136/rmdopen-2025-005547","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"RHEUMATOLOGY","Score":null,"Total":0}
Active vitamin D acts in vitro as an adjuvant to anti-TNFα treatment in a psoriatic synovial fibroblast activation model by modulating human Th17 activity.
Objectives: Psoriatic arthritis (PsA) is an IL-23/IL-17/TNF-driven inflammatory arthritis, commonly accompanied by vitamin D deficiency. Here, we investigate the interaction between PsA synovial fibroblasts (SFs) and human memory CCR6+Th17 (hmemCCR6+Th17) cells and evaluate the therapeutic effects of TNFα and/or IL-17A inhibitors, and the adjunctive therapy potential of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3).
Methods: SF derived from PsA biopsies were co-cultured with hmemCCR6+Th17 cells to construct a PsA SF activation model. SF phenotypes were analysed by flow cytometry. Treatments included adalimumab (anti-TNFα), secukinumab (anti-IL-17A), and/or 1,25(OH)2D3, applied alone or in combination. A transwell system was used to assess treatment effects on SF and hmemCCR6+Th17 cells. Cytokines and matrix metalloproteinases (MMPs) were quantified by ELISA.
Results: PsA SF were composed of heterogeneous subpopulations and constructed a pro-inflammatory feedback loop with hmemCCR6+Th17 cells. Anti-TNFα and/or anti-IL-17A significantly suppressed proinflammatory cytokines and tissue-destructive mediators in the PsA SF activation model, but showed limited effect on IL-22 and IFNγ. Adding 1,25(OH)2D3 to anti-TNFα treatment effectively overcame the limitations of single anti-TNFα in suppressing Th17 cytokines, while significantly enhancing the inhibition of IL-6, IL-8 and MMPs. In addition, 1,25(OH)2D3 promoted the production of IL-10.
Conclusions: TNFα or IL-17A inhibition alone does not completely inhibit the proinflammatory loop between hmemCCR6+Th17 cells and PsA SF, although the combination shows additive effect on suppressing proinflammatory and tissue-destructive mediators. Importantly, 1,25(OH)2D3 plays a complementary role in the treatment of this proinflammatory loop alongside anti-TNFα therapy and significantly induces IL-10. Clinical PsA studies are needed to explore the additional therapeutic potential of this combination.
期刊介绍：
RMD Open publishes high quality peer-reviewed original research covering the full spectrum of musculoskeletal disorders, rheumatism and connective tissue diseases, including osteoporosis, spine and rehabilitation. Clinical and epidemiological research, basic and translational medicine, interesting clinical cases, and smaller studies that add to the literature are all considered.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
