Objectives Interleukin (IL)-38 is a newly characterised cytokine that belongs to the IL-1 family. This cytokine is expressed in the rheumatoid arthritis (RA) synovial tissue and IL-38 deficient mice have exacerbated arthritis. Here, we analysed the effect of IL-38 overexpression in the joints of arthritic mice, in human macrophages and synovial fibroblasts in vitro.
Methods Articular injections of an adeno-associated virus (AAV) 2/8 encoding IL-38 were performed in collagen-induced arthritis (CIA), K/BxN serum transfer-induced arthritis (STIA) and antigen-induced arthritis (AIA) in mice. The effect of IL-38 overexpression was evaluated through clinical scores, immunohistochemistry, microCT, Luminex and RT-qPCR analysis. THP-1 macrophages were transduced with a lentiviral vector to overexpress IL-38.
Results Clinical inflammatory scores were significantly decreased after AAV IL-38 injection in joints of mice with CIA and STIA, but not AIA. This decrease was accompanied by reduced macrophage infiltration and a decreased expression of Th17 cytokines (IL-17, IL-23, IL-22) and TNFα. However, IL-38 overexpression had no effect on cartilage or bone destruction. In vitro, the THP-1 monocytic cell line expressed less IL-6, TNFα and IL-23 after IL-38 overexpression. Conditioned media from these cells, containing released IL-38, also exert an anti-inflammatory effect on human primary macrophages and synovial fibroblasts from patients with RA.
Conclusions This study shows for the first time that IL-38 overexpression attenuates the severity of experimental arthritis. IL-38 may exert its anti-inflammatory effects by decreasing the production of proinflammatory cytokines by macrophages and synovial fibroblasts. This effect can lead to the development of novel treatment strategies in arthritis.
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Handling editor Tore K Kvien
FB and BLG are senior coauthors.
Contributors M-AB performed mouse arthritis models, in vitro study and associated analysis and wrote the manuscript, AN did some in vitro experiments and GB performed some histology and microCT analysis. RB contributed to Luminex experiments. ST provided synovial biopsies. VT contributed to AAV design. PL contributed to study design. CG and GP provided K/BxN serum, lentiviral plasmids and contributed to the elaboration of the manuscript. BLG performed mouse arthritis models, planned studies, analysed data and wrote the manuscript. FB planned studies, analysed data and wrote the manuscript. All authors read and approved the final manuscript.
Funding This work was supported by Inserm and in part by the Arthritis Foundation and by the French Society of Rheumatology. M-AB was a recipient from a fellowship from the French Ministry of Research. CG is supported by grants from the Swiss National Science Foundation (310030_152638), the Rheumasearch Foundation, the Uniscientia Foundation and the Institute of Arthritis Research.
Competing interests None declared.
Ethics approval Local ethics committee of the Nantes Hospitals and the French Research Ministry (no. 2008-402). All research involving animals is conducted following institutional guidelines and has been approved by the French ethical committee CEEA.PdL (License 2012.86) and by local veterinary services.
Provenance and peer review Not commissioned; externally peer reviewed.