AB0055 Rho a protein and erk/jnk pathways regulate il-23 production by tlr2 in synovial macrophages from patients with rheumatoid arthritis. (23rd January 2014)

• Record Type: Journal Article
• Authors: Park, S. Y.; Kim, H. Y.; Lee, H. R.; Baek, S. H.; Kim, C. D.
• Is Part Of: Annals of the rheumatic diseases. Volume 72:Supplement 3(2013)
• Page Start: A802
• Page End: A802
• Publication Date: 2014-01-23
• Subjects: Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2013-eular.2378
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Background: TLR2 expression upon application of TNF-a, IL-1b, and LPSin synovial fibroblasts from joints of RA patients (1, 2 ).IL-23 is involved in autoimmune diseases such as RA and psoriasis, in which the cellular mechanism of IL-23 is associated with self-reactive production of IL-17, IL-6, and TNF-a, thereby playing a critical role in development of autoimmune inflammation (3, 4 ). Objectives: This study aimed to elucidate the signaling pathways of TLR2-mediated IL-23 production in synovial fluid macrophages from patients with rheumatoid arthritis (RA). Methods: Expression of IL-23 was measured by ELISA and immunofluorescence in synovial fluid macrophages from RA patients. RhoA activity was assessed by pull-down assay. The role of MAP kinase was investigated using selective inhibitors and western blot. Results: TLR2 ligand LTA-stimulated IL-23 production measured by ELISAwas elevated time- and concentration-dependently. TLR2 stimulation by LTA significantly increased not only GTP-bound RhoA activity but also phosphorylation of ERK and JNK in RA macrophages in association with increased nuclear translocation and DNA-binding activity of NF-kB. Inhibition of RhoA by Y27632, and of ERK and JNK phosphorylation by PD98059 and SP600125, resulted in suppression of LTA-induced NF-kB activation and IL-23 production. Image/graph: Conclusions: TLR2-mediated IL-23 production in synovial fluid macrophages was mediated through activation of RhoA GTPase and phosphorylation of ERK/JNK in association with NF-kB activation. References: Brentano F, Kyburz D, Schorr O, Gay R, Gay S. The role of Toll-like receptor signalling in the pathogenesis of arthritis. Cell Immunol 2005, 233:90-96. Seibl R, Birchler T, Loeliger S, Hossle JP, Gay RE, Saurenmann T, Michel BA, Seger RA, Gay S, Lauener RP. Expression and regulation of Toll-like receptor 2 in rheumatoid arthritis synovium. Am J Pathol 2003, 162:1221-1227. Murphy CA, Langrish CL, Chen Y, Blumenschein W, McClanahan T, Kastelein RA, Sedgwick JD, Cua DJ. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J Exp Med 2003, 198:1951-1957. Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, McClanahan T, Kastelein RA, Cua DJ. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 2005, 201: 233-240. Disclosure of Interest: None Declared