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

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.

• Authors: Sue-Yun Hwang, Ju-Young Kim, Kyoung-Woon Kim, Mi-Kyung Park, Youngmee Moon, Wan-Uk Kim, Ho-Youn Kim
• Journal: Arthritis research & therapy (Arthritis Res Ther) Vol. 6 Issue 2 Pg. R120-8 ( 2004) ISSN: 1478-6362 [Electronic] England
• PMID: 15059275 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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
• AKT1 protein, human
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• Mitogen-Activated Protein Kinases

Topics

• Arthritis, Rheumatoid (enzymology, pathology)
• Cells, Cultured
• Fibroblasts (enzymology, metabolism, 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, 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, pathology)
• Transcription Factor RelA