IL-22/IL-22R1 axis and S100A8/A9 alarmins in human osteoarthritic and rheumatoid arthritis synovial fibroblasts

Rheumatology (Oxford). 2013 Dec;52(12):2177-86. doi: 10.1093/rheumatology/ket315. Epub 2013 Sep 19.


Objectives: Fibroblast-like synoviocytes (FLSs) are crucial players in the pathogenesis of synovitis in rheumatic diseases. Targeting FLS activation represents an approach to the development of therapeutic strategies. Our aim was to investigate whether the microenvironment of inflamed joints could modulate the expression of IL-22 and IL-22R1 on OA and RA FLSs. We also examined the effect of IL-22 on FLS activation as well as on their IL-17-related responses.

Methods: IL-22 and IL-22R1 expression was studied by RT-PCR and immunoblotting. Proliferation was measured by an ELISA kit. IL-17 receptors, p19IL-23 and alarmins were analysed by RT-PCR. IL-17 receptor expression was evaluated by flow cytometry. MMP1 and IL-23 were measured by ELISA. S100A8/A9 expression was detected by immunofluorescence and ELISA. Signal transducer and activator of transcription 3 (STAT3) phosphorylation was quantified using a cell-based ELISA kit.

Results: IL-22 and IL-22R1 were expressed constitutively in FLSs. We demonstrated that S100A8 and S100A9 were synthesized in FLSs. We reported that inflammatory mediators increased the expression of the IL-22/IL-22R1 axis, amplifying FLS activation. IL-22 enhanced FLS proliferation and up-regulated MMP1 and S100A8/A9 production. STAT3 phosphorylation was induced after IL-22 treatment and the stimulatory effect of IL-22 on S100A8/A9 was reduced after the activities of Janus kinase 2 (JAK2) and JAK3 were blocked. We showed an inhibitory action of IL-22 on IL-23 and IL-17RC expression in RA FLSs and on IL-17RA in OA FLSs.

Conclusion: Therapies based on the pharmacological disruption signalling of IL-22 could be beneficial for the treatment of rheumatic diseases. The restricted expression of IL-22R1 to non-lymphoid cells could lead to a reduction of side effects mediated by immune responses.

Keywords: IL-22; IL-22R1; alarmins; osteoarthritis; rheumatoid arthritis; synovial fibroblast.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arthritis, Rheumatoid / metabolism*
  • Arthritis, Rheumatoid / pathology
  • Calgranulin A / metabolism*
  • Calgranulin B / metabolism*
  • Cell Proliferation
  • Down-Regulation
  • Fibroblasts / metabolism*
  • Fibroblasts / pathology
  • Humans
  • Hyperplasia / pathology
  • Interleukins / metabolism*
  • Interleukins / pharmacology
  • Janus Kinase 2 / metabolism
  • Janus Kinase 3 / metabolism
  • Matrix Metalloproteinases / biosynthesis
  • Osteoarthritis / metabolism*
  • Phosphorylation
  • Receptors, Interleukin / metabolism
  • Receptors, Interleukin-17 / metabolism
  • STAT3 Transcription Factor / metabolism
  • Synovial Membrane / metabolism
  • Synovial Membrane / pathology
  • Toll-Like Receptors / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology
  • Up-Regulation


  • Calgranulin A
  • Calgranulin B
  • Interleukins
  • Receptors, Interleukin
  • Receptors, Interleukin-17
  • STAT3 Transcription Factor
  • Toll-Like Receptors
  • Tumor Necrosis Factor-alpha
  • interleukin-22 receptor
  • Janus Kinase 2
  • Janus Kinase 3
  • Matrix Metalloproteinases
  • interleukin-22