IL-17 induces production of IL-6 and IL-8 in rheumatoid arthritis synovial fibroblasts via NF-kappaB- and PI3-kinase/Akt-dependent pathways

Arthritis Res Ther. 2004;6(2):R120-8. doi: 10.1186/ar1038. Epub 2004 Jan 21.

Abstract

Recent studies of the pathogenesis of rheumatoid arthritis (RA) have revealed that both synovial fibroblasts and T cells participate in the perpetuation of joint inflammation as dynamic partners in a mutual activation feedback, via secretion of cytokines and chemokines that stimulate each other. In this study, we investigated the role of IL-17, a major Th1 cytokine produced by activated T cells, in the activation of RA synovial fibroblasts. Transcripts of IL-17R (IL-17 receptor) and IL-17RB (IL-17 receptor B) were present in fibroblast-like synoviocytes (FLS) of RA patients. IL-17R responded with increased expression upon in vitro stimulation with IL-17, while the level of IL-17RB did not change. IL-17 enhanced the production of IL-6 and IL-8 in FLS, as previously shown, but did not affect the synthesis of IL-15. IL-17 appears to be a stronger inducer of IL-6 and IL-8 than IL-15, and even exerted activation comparable to that of IL-1beta in RA FLS. IL-17-mediated induction of IL-6 and IL-8 was transduced via activation of phosphatidylinositol 3-kinase/Akt and NF-kappaB, while CD40 ligation and p38 MAPK (mitogen-activated protein kinase) are not likely to partake in the process. Together these results suggest that IL-17 is capable of more than accessory roles in the activation of RA FLS and provide grounds for targeting IL-17-associated pathways in therapeutic modulation of arthritis inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arthritis, Rheumatoid / enzymology
  • Arthritis, Rheumatoid / pathology*
  • Cells, Cultured
  • Fibroblasts / enzymology
  • Fibroblasts / metabolism*
  • Fibroblasts / pathology
  • Humans
  • Interleukin-15 / biosynthesis
  • Interleukin-17 / physiology*
  • Interleukin-6 / biosynthesis*
  • Interleukin-8 / biosynthesis*
  • Middle Aged
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • NF-kappa B / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphatidylinositol 3-Kinases / physiology
  • Protein-Serine-Threonine Kinases / physiology
  • Proto-Oncogene Proteins / physiology
  • Proto-Oncogene Proteins c-akt
  • Receptors, Interleukin / biosynthesis
  • Receptors, Interleukin-17
  • Signal Transduction / physiology
  • Synovial Membrane / enzymology
  • Synovial Membrane / pathology*
  • Transcription Factor RelA

Substances

  • IL17RA protein, human
  • Interleukin-15
  • Interleukin-17
  • Interleukin-6
  • Interleukin-8
  • NF-kappa B
  • Proto-Oncogene Proteins
  • Receptors, Interleukin
  • Receptors, Interleukin-17
  • Transcription Factor RelA
  • Phosphatidylinositol 3-Kinases
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinases