Interleukin-18 induces rheumatoid arthritis synovial fibroblast CXC chemokine production through NF kappa B activation

Interleukin-18 (IL-18) is a novel proinflammatory cytokine that was recentl y found in synovial fluids and in synovial tissues from patients with rheum atoid arthritis (RA). To determine the participation of IL-18 in the inflam mation observed in RA, we investigated the effect of IL-18 on RA synovial f ibroblast chemokine production. Using FACS analysis, we showed that IL-18 i nduced a doubling in the production of intracellular IL-8 by RA synovial fi broblasts, and this result was confirmed by Western blot. At the extracellu lar level, IL-18 up-regulated the secretion of IL-8 in a dose- and time-dep endent 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 immunof luorescence and Western blot, we demonstrated that IL-18 activates the tran slocation of the transcription factor nuclear factor kappa B (NF kappaB) in to the nucleus of RA synovial fibroblasts. IL-18 induces IL-8 secretion thr ough NF kappaB because RA synovial fibroblasts pretreated with antisense to NF kappaB p65 oligonucleoticle produce a mean of 44% less IL-8 compared wi th cells pretreated with the control sense oligonucleotide. These results i ndicate a novel role for IL-18 in inducing RA synovial fibroblast expressio n of CXC chemokines through NF kappaB and place this cytokine in a strategi c role in the local inflammation observed in RA.