IL-17 induces production of IL-6 and IL-8 in rheumatoid arthritis synovial fibroblasts via NF-kappaB- and PI3-kinase/Akt-dependent pathways.
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.
Hwang
Sue-Yun
SY
Rheumatism Research Center, Catholic Institutes of Medical Science, The Catholic University of Korea, Seoul, Korea. dutuya@cmc.cuk.ac.kr
Kim
Ju-Young
JY
Kim
Kyoung-Woon
KW
Park
Mi-Kyung
MK
Moon
Youngmee
Y
Kim
Wan-Uk
WU
Kim
Ho-Youn
HY
D001172:Arthritis, Rheumatoid / Q000201:enzymology / Q000473:pathology*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D019409:Interleukin-15 / Q000096:biosynthesis; D020381:Interleukin-17 / Q000502:physiology*; D015850:Interleukin-6 / Q000096:biosynthesis*; D016209:Interleukin-8 / Q000096:biosynthesis*; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D016328:NF-kappa B / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism* / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D018123:Receptors, Interleukin / Q000096:biosynthesis; D053722:Receptors, Interleukin-17; D015398:Signal Transduction / Q000502:physiology; D013583:Synovial Membrane / Q000201:enzymology / Q000473:pathology*; D051996:Transcription Factor RelA
D019409:Interleukin-15; D020381:Interleukin-17; D015850:Interleukin-6; D016209:Interleukin-8; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D018123:Receptors, Interleukin; D053722:Receptors, Interleukin-17; D051996:Transcription Factor RelA; C109985:IL17RA protein, human; C494918:AKT1 protein, human