1,25(OH)D and Dexamethasone Additively Suppress Synovial Fibroblast Activation by CCR6 T Helper Memory Cells and Enhance the Effect of Tumor Necrosis Factor Alpha Blockade

Overview

Journal Arthritis Res Ther

Publisher Biomed Central

Specialty Rheumatology

Date 2018 Sep 22

PMID 30236152

Citations 16

Authors

Wendy Dankers

Claudia Gonzalez-Leal

Nadine Davelaar

Patrick S Asmawidjaja

Adriana M C Mus

Johanna M W Hazes

Edgar M Colin

Erik Lubberts

Affiliations

Soon will be listed here.

Abstract

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)D 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)D, DEX, or etanercept. Treatment effects were assessed using enzyme-linked immunosorbent assay (ELISA) and flow cytometry.

Results: 1,25(OH)D, 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)D 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)D and DEX additively inhibited inflammatory mediators in CCR6 memTh-RASF cocultures. Interestingly, low doses of mainly DEX, but also 1,25(OH)D, combined with etanercept better suppressed synovial inflammation in this coculture model compared with etanercept alone.

Conclusion: This study suggests that 1,25(OH)D and DEX additively inhibit synovial inflammation through targeting predominantly CCR6 memTh cells and RASF, respectively. Furthermore, low doses of DEX and 1,25(OH)D enhance the effect of TNFα blockade in inhibiting RASF activation, thus providing a basis to improve RA treatment.

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