Rheumatology Advance Access originally published online on June 14, 2007
Rheumatology 2007 46(8):1266-1273; doi:10.1093/rheumatology/kem055
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Interleukin (IL)-23 p19 expression induced by IL-1ß in human fibroblast-like synoviocytes with rheumatoid arthritis via active nuclear factor-
B and AP-1 dependent pathway
Graduate Institute of Medical Sciences, 1Rheumatology/Immunology/Allergy, Tri-Service General Hospital, National Defense Medical Center, Taipei and 2Department of Medical Laboratory Science and Biotechnology, Yuanpei University, Hsinchu, Taiwan, Republic of China.
Correspondence to: Deh-Ming Chang, MD, Rheumatology/Immunology/Allergy, Tri-Service General Hospital, #325 Cheng-Kung Road, Section 2, Neihu 114, Taipei, Taiwan, Republic of China. E-mail: ming0503{at}ms3.hinet.net
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Abstract |
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Objectives. To explore the source of the p19 subunit of interleukin-23 (IL-23) in joints with rheumatoid arthritis (RA), the effects of IL-1ß and tumour necrosis factor (TNF)-
on IL-23 gene expression in RA fibroblast-like synoviocytes and the effect of IL-23 on proinflammatory cytokines.
Methods. Expression of IL-23 p19 in joints was examined by immunohistochemical analysis of patients with RA and osteoarthritis (OA). The effects of IL-1ß and TNF- on the expression, of IL-23 p19 and IL-12 p35 subunits in human fibroblast-like synoviocytes from RA patients (HFLS-RA) were determined by reverse transcriptase polymerase chain reaction (RT-PCR), quantitative PCR and western blotting assay. Blockade of nuclear factor kappaB (NF-
B) or AP-1 activation was used to verify the involvement of intracellular signal pathways of the induction of p19. IL-23-induced IL-8 and IL-6 productions were determined in HFLS-RA by RT-PCR and enzyme-linked immunosorbent assay.
Results. IL-23 p19 was expressed in the synovium from RA, but not from OA patients. Similar to the protein expression, IL-23 p19 mRNA could be detected by RT-PCR in four of five RA synovial fluid mononuclear cells (SFMC). IL-1ß and TNF- could induce RA fibroblast-like synoviocytes to produce the IL-23 p19 subunit. The effects of IL-1ß were much stronger than TNF-. These responses were observed in both a dose-responsive and time-dependent manner. IL-1ß produced weakly enhanced gene expression of the p35 subunits of IL-12. IL-1ß also promotes the p35 expression, a subunit of IL-12, but weakly. In addition, the NF-B and the AP-1 inhibitors down-regulated the expression of IL-23 p19 mRNA induced by IL-1ß. IL-23 receptor (IL-23R) was of constitutive expression in HFLS-RA. Moreover, IL-23 up-regulated the IL-8 and IL-6 mRNA and protein levels in a dose-dependent manner in HFLS-RA.
Conclusions. Our results demonstrate that IL-23, produced by mononuclear cells in synovial fluid with RA and HFLS-RA, promotes inflammatory responses in RA by inducing IL-8 and IL-6 production from HFLS. IL-1ß regulates IL-23 p19 expression via NF-B and AP-1 pathways. This report also demonstrates that IL-23 could promote inflammatory responses in HFLS-RA by stimulating IL-8 and IL-6 production.
KEY WORDS: IL-23, Rheumatoid arthritis, HFLS-RA, IL-1ß
Submitted 5 November 2006;
revised version accepted 8 February 2007.
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