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OP0093 Il-38 overexpression induces anti-inflammatory effects in mice arthritis models and in human macrophages in vitro
  1. M-A Boutet1,
  2. A Najm2,
  3. G Bart2,
  4. R Brion1,
  5. S Touchais2,
  6. V Trichet1,
  7. P Layrolle1,
  8. C Gabay3,
  9. G Palmer-Lourenco3,
  10. F Blanchard1,
  11. B Le Goff2
  1. 1Inserm UMR957, Université de Nantes
  2. 2Rheumatology Unit, Nantes University Hospital, Nantes, France
  3. 3Department of pathology and immunology, University of Geneva school of medicine, Geneva, Switzerland

Abstract

Background IL-38 is a newly characterized cytokine that belongs to the IL-1 family. This cytokine is expressed in the rheumatoid arthritis (RA) synovial tissue (1) and IL-38 deficient mice have exacerbated arthritis (2).

Objectives This work aims to analyze 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 (AAV2/8) 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 monocytes/macrophages were transduced with a lentiviral vector to overexpress IL-38. Effect of conditioned media from these transduced THP-1 cells was also tested on primary culture: M1 macrophages and fibroblast-like synoviocytes from RA patients (RA-FLS).

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 expressed cytokines (IL-17, IL-23, IL-22, 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, was also able to exert an anti-inflammatory effect on human primary M1 macrophages and RA-FLS by reducing their IL-23 (M1) and IL-6 (M1 and RA-FLS) expression.

Conclusions This study shows for the first time that IL-38 overexpression attenuates the severity of experimental arthritis in two mice arthritis models. IL-38 may exert its anti-inflammatory effects by decreasing the production of pro-inflammatory cytokines by macrophages and synovial fibroblasts. This effect can lead to the development of novel treatment strategies in arthritis.

References

  1. Boutet MA, Bart G, Gahier M, Amiaud J, Brulin B, Charrier C, Morel F, Lecron JC, RolliDerkinderen M, Boureille A, et al. Distinct expression of IL-36α, β, γ and their antagonists IL-36Ra and IL-38 in Psoriasis, Rheumatoid Arthritis and Crohn's disease. Clin Exp Immunol, 2015. doi: 10.1111/cei.12761.

  2. Takenaka, S., Kaieda, S., Kawayama, T., Matsuoka, M., Kaku, Y., Kinoshita, T., Sakazaki, Y., Okamoto, M., Tominaga, M., Kanesaki, K., et al. (2015). IL-38: A new factor in rheumatoid arthritis. Biochem. Biophys. Rep. 4, 386–391.

References

Disclosure of Interest None declared

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