IL-38 overexpression induces anti-inflammatory effects in mice arthritis models and in human macrophages in vitro

Ann Rheum Dis. 2017 Jul;76(7):1304-1312. doi: 10.1136/annrheumdis-2016-210630. Epub 2017 Mar 13.

Abstract

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.

Keywords: Arthritis; Cytokines; Inflammation.

MeSH terms

  • Animals
  • Arthritis, Experimental / genetics
  • Arthritis, Experimental / immunology*
  • Arthritis, Rheumatoid / immunology*
  • Blotting, Western
  • Bone and Bones / diagnostic imaging
  • Cartilage, Articular / diagnostic imaging
  • Cell Line
  • Culture Media, Conditioned
  • Enzyme-Linked Immunosorbent Assay
  • Fibroblasts / immunology*
  • Humans
  • Immunohistochemistry
  • In Vitro Techniques
  • Interleukin-17 / genetics
  • Interleukin-17 / immunology
  • Interleukin-23 / genetics
  • Interleukin-23 / immunology
  • Interleukin-6 / genetics
  • Interleukin-6 / immunology
  • Interleukins / genetics
  • Interleukins / immunology*
  • Macrophages / immunology*
  • Mice
  • Real-Time Polymerase Chain Reaction
  • Synovial Membrane / cytology
  • Th17 Cells / immunology
  • Transcriptome
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / immunology
  • X-Ray Microtomography

Substances

  • Culture Media, Conditioned
  • IL-38 protein, human
  • Interleukin-17
  • Interleukin-23
  • Interleukin-6
  • Interleukins
  • Tumor Necrosis Factor-alpha
  • interleukin-22