Interleukin-18 induces rheumatoid arthritis synovial fibroblast CXC chemokine production through NFκB activation

Interleukin-18 (IL-18) is a novel proinflammatory cytokine that was recently found in synovial fluids and in synovial tissues from patients with rheumatoid arthritis (RA). To determine the participation of IL-18 in the inflammation observed in RA, we investigated the effect of IL-18 on RA synovial fibroblast chemokine production. Using FACS analysis, we showed that IL-18 induced a doubling in the production of intracellular IL-8 by RA synovial fibroblasts, and this result was confirmed by Western blot. At the extracellular level, IL-18 up-regulated the secretion of IL-8 in a dose- and time-dependent manner. IL-18 also up-regulated the other CXC chemokines, epithelial-neutrophil activating protein (ENA-78) and growth-regulated oncogene (gro alpha), in a dose dependent manner, but failed to induce the production of the CC chemokine, macrophage inflammatory protein (MIP)-1 alpha. By immunofluorescence and Western blot, we demonstrated that IL-18 activates the translocation of the transcription factor nuclear factor kappa B (NF kappaB) into the nucleus of RA synovial fibroblasts. IL-18 induces IL-8 secretion through NF kappaB because RA synovial fibroblasts pretreated with antisense to NF kappaB p65 oligonucleoticle produce a mean of 44% less IL-8 compared with cells pretreated with the control sense oligonucleotide. These results indicate a novel role for IL-18 in inducing RA synovial fibroblast expression of CXC chemokines through NF kappaB and place this cytokine in a strategic role in the local inflammation observed in RA.