Academic Journal
Inflammation-Inducible Expression of Human Indoleamine 2,3-Dioxygenase Driven by the E-Selectin Promoter Ameliorates Collagen-Induced Arthritis.
| Τίτλος: | Inflammation-Inducible Expression of Human Indoleamine 2,3-Dioxygenase Driven by the E-Selectin Promoter Ameliorates Collagen-Induced Arthritis. |
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| Συγγραφείς: | Karaçay M; Department of Medicine-Immunology, Institute of Health Sciences, Bursa Uludag University, Bursa, Türkiye.; Division of Medical Genetics, Department of Internal Medicine, Faculty of Medicine, Van Yuzuncu Yil University, Van, Türkiye., Yılmaz İ; Department of Medicine-Immunology, Institute of Health Sciences, Bursa Uludag University, Bursa, Türkiye., Barazi Soydaş AÖ; Department of Immunology, Graduate School of Health Sciences, Gazi University, Ankara, Türkiye., Güvenç-Bayram G; Department of Physiology, Faculty of Veterinary Medicine, Dokuz Eylul University, Izmir, Türkiye., Ersoy F; Department of Molecular Biology and Genetics, Bursa Uludag University, Bursa, Türkiye., Özgüden Akkoç CG; Department of Histology and Embryology, Faculty of Veterinary Medicine, Bursa Uludag University, Bursa, Türkiye., Yılmaztepe Oral A; Department of Medical Biochemistry, Faculty of Medicine, Bursa Uludag University, Bursa, Türkiye., Akkoç A; Department of Pathology, Faculty of Veterinary Medicine, Bursa Uludag University, Bursa, Türkiye., Yalçın M; Department of Physiology, Faculty of Veterinary Medicine, Bursa Uludag University, Bursa, Türkiye., Oral HB; Department of Immunology, Faculty of Medicine, Bursa Uludag University, Bursa, Türkiye. |
| Πηγή: | Human gene therapy [Hum Gene Ther] 2026 Sep; Vol. 37 (17-18), pp. 833-848. Date of Electronic Publication: 2026 Jun 04. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: M.A. Liebert Country of Publication: United States NLM ID: 9008950 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1557-7422 (Electronic) Linking ISSN: 10430342 NLM ISO Abbreviation: Hum Gene Ther Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: New York : M.A. Liebert, c1990- |
| Ιατρικοί όροι (MeSH): | Indoleamine-Pyrrole 2,3,-Dioxygenase*/genetics , Indoleamine-Pyrrole 2,3,-Dioxygenase*/metabolism , Arthritis, Experimental*/therapy , Arthritis, Experimental*/genetics , Arthritis, Experimental*/pathology , E-Selectin*/genetics , Inflammation*/genetics , Promoter Regions, Genetic* , Genetic Therapy*, Interleukin-1beta/metabolism ; Antigens, CD/genetics ; Antigens, CD/metabolism ; CD4-Positive T-Lymphocytes/immunology ; Antigens, Differentiation, Myelomonocytic/genetics ; Antigens, Differentiation, Myelomonocytic/metabolism ; Animals ; Humans ; Mice ; HeLa Cells ; Disease Models, Animal ; Mice, Inbred BALB C ; Gene Therapy Agents |
| Περίληψη: | Rheumatoid arthritis is a chronic autoimmune disease characterized by persistent synovial inflammation and progressive joint destruction. Although biological disease-modifying anti-rheumatic drugs (DMARDs) have transformed treatment, their systemic immunosuppression, high cost, and incomplete efficacy in certain joints remain significant challenges. To address these limitations, we developed a localized gene therapy using the human indoleamine 2,3-dioxygenase (hIDO) gene driven by the E-selectin (ELAM-1) promoter, which is responsive to inflammatory cytokines. We assessed ELAM-1 promoter responsiveness to interleukin-1β (IL-1β) stimulation in vitro mainly using the HeLa cell line, measuring hIDO expression and enzymatic activity by enzyme-linked immunosorbent assay, quantitative reverse transcription-polymerase chain reaction (qRT-PCR), Western blotting and kynurenine assays. In vivo, we established a robust collagen-induced arthritis (CIA) model in BALB/c mice, which are normally resistant to CIA, and delivered pELAM-1pro/hIDO plasmids intra-articularly via liposomes. Therapeutic efficacy was evaluated by clinical scoring, ankle circumference, histopathology, immunohistochemical quantification of synovial CD4+ T cells and CD68+ macrophages, and endpoint immunohistochemical assessment of IDO expression. In vitro, the ELAM-1 promoter allowed rapid, high-level expression of hIDO within 2 h of IL-1β stimulation, without IDO-induced suppression of the promoter. In vivo, pELAM-1pro/hIDO treatment significantly reduced ankle swelling and clinical arthritis scores more rapidly than constitutive CMV-driven hIDO, achieving marked histological improvement on day 7. The treated joints exhibited substantial reductions in pathogenic CD4+ T cells and CD68+ macrophages, consistent with the IDO immunoregulatory mechanism. This study supports the feasibility of a localized gene therapy approach using an inflammation-responsive promoter and suggests localized immunomodulation at disease sites in a manner consistent with inflammation-associated promoter activity. |
| Contributed Indexing: | Keywords: E-selectin promoter; gene therapy; indoleamine 2,3-dioxygenase; rheumatoid arthritis |
| Substance Nomenclature: | 0 (Indoleamine-Pyrrole 2,3,-Dioxygenase) 0 (E-Selectin) 0 (Interleukin-1beta) 0 (Antigens, CD) 0 (Antigens, Differentiation, Myelomonocytic) |
| Entry Date(s): | Date Created: 20260604 Date Completed: 20260826 Latest Revision: 20260826 |
| Update Code: | 20260826 |
| DOI: | 10.1177/10430342261452520 |
| PMID: | 42237653 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1557-7422 |
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| DOI: | 10.1177/10430342261452520 |