OBJECTIVE: To investigate the expression of interleukin (IL)-23p19 in human rheumatoid arthritis (RA) synovial fibroblasts and its up-regulation by IL-17 stimulation, and to define the signal pathways involved in the regulation of IL-23p19 expression in RA synovial fibroblasts. METHODS: Synovial fluid (SF) and serum levels of IL-23p19 in RA were determined by enzyme-linked immunosorbent assays. The levels of IL-23p19 mRNA and protein were measured after the RA synovial fibroblasts were treated with recombinant human IL-17 and various inhibitors of intracellular signal pathway molecules using reverse transcription (RT) polymerase chain reaction (PCR), real-time PCR and western blotting. RESULTS: Levels of IL-23p19 in the sera and SF were much higher in RA patients than in osteoarthritis patients or healthy controls. The expression of IL-23p19 mRNA and protein was enhanced in RA synovial fibroblasts by IL-17 stimulation. Such effects of IL-17 were completely blocked by inhibitors of phosphatidylinositol (PI)-kinase/Akt, nuclear factor (NF)-kappaB and p38 mitogen-activated protein kinase (MAPK). In accordance with the expression of IL-23p19, the phosphorylation of IkappaB, Akt and p38 MAPK in synovial fibroblasts also increased after IL-17 stimulation. CONCLUSION: IL-23p19 is over-expressed in RA synovial fibroblasts and IL-17 appears to up-regulate the expression of IL-23p19 in RA synovial fibroblasts via PI3-kinase/Akt, NF-kappaB- and p38-MAPK-mediated pathways. These results suggest that a disruption of interaction between IL-17 and IL-23p19 may provide a new therapeutic approach in the treatment of RA.
OBJECTIVE: To investigate the expression of interleukin (IL)-23p19 in humanrheumatoid arthritis (RA) synovial fibroblasts and its up-regulation by IL-17 stimulation, and to define the signal pathways involved in the regulation of IL-23p19 expression in RA synovial fibroblasts. METHODS: Synovial fluid (SF) and serum levels of IL-23p19 in RA were determined by enzyme-linked immunosorbent assays. The levels of IL-23p19 mRNA and protein were measured after the RA synovial fibroblasts were treated with recombinant humanIL-17 and various inhibitors of intracellular signal pathway molecules using reverse transcription (RT) polymerase chain reaction (PCR), real-time PCR and western blotting. RESULTS: Levels of IL-23p19 in the sera and SF were much higher in RA patients than in osteoarthritispatients or healthy controls. The expression of IL-23p19 mRNA and protein was enhanced in RA synovial fibroblasts by IL-17 stimulation. Such effects of IL-17 were completely blocked by inhibitors of phosphatidylinositol (PI)-kinase/Akt, nuclear factor (NF)-kappaB and p38 mitogen-activated protein kinase (MAPK). In accordance with the expression of IL-23p19, the phosphorylation of IkappaB, Akt and p38 MAPK in synovial fibroblasts also increased after IL-17 stimulation. CONCLUSION:IL-23p19 is over-expressed in RA synovial fibroblasts and IL-17 appears to up-regulate the expression of IL-23p19 in RA synovial fibroblasts via PI3-kinase/Akt, NF-kappaB- and p38-MAPK-mediated pathways. These results suggest that a disruption of interaction between IL-17 and IL-23p19 may provide a new therapeutic approach in the treatment of RA.
Authors: Lydia R Coulthard; Danielle E White; Dominic L Jones; Michael F McDermott; Susan A Burchill Journal: Trends Mol Med Date: 2009-08-06 Impact factor: 11.951