1,25(OH)2D3 and dexamethasone additively suppress synovial fibroblast activation by CCR6+ T helper memory cells and enhance the effect of tumor necrosis factor alpha blockade

Autor: Patrick S. Asmawidjaja, E. M. Colin, Johanna M. W. Hazes, Adriana M. C. Mus, Erik Lubberts, Claudia González-Leal, Wendy Dankers, Nadine Davelaar
Přispěvatelé: Clinical Immunology and Rheumatology, Immunology, Rheumatology, Internal Medicine
Jazyk: angličtina
Rok vydání: 2018
Předmět:
0301 basic medicine
Dexamethasone/administration & dosage
Helper-Inducer/drug effects
lcsh:Diseases of the musculoskeletal system
CCR6/biosynthesis
T-Lymphocytes
Inflammation
Pharmacology
Calcitriol/administration & dosage
Peripheral blood mononuclear cell
Dexamethasone
Etanercept
03 medical and health sciences
0302 clinical medicine
Interferon
Receptors
medicine
Leukocytes
Synovial Membrane/drug effects
Humans
Rheumatoid arthritis
Vitamin D
Receptors
CCR6/biosynthesis
Leukocytes
Mononuclear/drug effects
Chemistry
Tumor Necrosis Factor-alpha/antagonists & inhibitors
Mononuclear/drug effects
Interleukin
Drug Synergism
medicine.disease
Coculture Techniques
Fibroblasts/drug effects
030104 developmental biology
Tumor necrosis factor alpha
T-Lymphocytes
Helper-Inducer/drug effects
Th17
lcsh:RC925-935
medicine.symptom
CCR6
030215 immunology
medicine.drug
Zdroj: Arthritis research & therapy, 20(1). BioMed Central
Arthritis Research & Therapy, Vol 20, Iss 1, Pp 1-10 (2018)
Arthritis Research & Therapy, 20:212. BioMed Central Ltd.
ISSN: 1478-6354
1478-6362
Popis: Background Despite recent improvements in the treatment of rheumatoid arthritis (RA), an insufficient treatment response and the development of treatment resistance in many patients illustrates the need for new therapeutic strategies. Chronic synovial inflammation could be suppressed by targeting RA synovial fibroblast (RASF) activation by, for example, interleukin (IL)-17A-producing CCR6+ T helper memory (memTh) cells. Here, we modulated this interaction by combining the active vitamin D metabolite 1,25(OH)2D3 with dexamethasone (DEX) and explored the potential therapeutic applications. Methods CCR6+ memTh cells from peripheral blood mononuclear cells (PBMCs) of healthy donors or treatment-naive early RA patients were cultured alone or with RASF from established RA patients for 3 days and treated with or without 1,25(OH)2D3, DEX, or etanercept. Treatment effects were assessed using enzyme-linked immunosorbent assay (ELISA) and flow cytometry. Results 1,25(OH)2D3, and to lesser extent DEX, reduced production of the pro-inflammatory cytokines IL-17A, IL-22, and interferon (IFN)γ in CCR6+ memTh cells. Tumor necrosis factor (TNF)α was only inhibited by the combination of 1,25(OH)2D3 and DEX. In contrast, DEX was the strongest inhibitor of IL-6, IL-8, and tissue-destructive enzymes in RASF. As a result, 1,25(OH)2D3 and DEX additively inhibited inflammatory mediators in CCR6+ memTh-RASF cocultures. Interestingly, low doses of mainly DEX, but also 1,25(OH)2D3, combined with etanercept better suppressed synovial inflammation in this coculture model compared with etanercept alone. Conclusion This study suggests that 1,25(OH)2D3 and DEX additively inhibit synovial inflammation through targeting predominantly CCR6+ memTh cells and RASF, respectively. Furthermore, low doses of DEX and 1,25(OH)2D3 enhance the effect of TNFα blockade in inhibiting RASF activation, thus providing a basis to improve RA treatment.
Databáze: OpenAIRE
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