Interleukin-18 induces rheumatoid arthritis synovial fibroblast CXC chemokine production through NFkappaB 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 (groalpha), in a dose dependent manner, but failed to induce the production of the CC chemokine, macrophage inflammatory protein (MIP)-1alpha. By immunofluorescence and Western blot, we demonstrated that IL-18 activates the translocation of the transcription factor nuclear factor kappa B (NFkappaB) into the nucleus of RA synovial fibroblasts. IL-18 induces IL-8 secretion through NFkappaB because RA synovial fibroblasts pretreated with antisense to NFkappaB p65 oligonucleotide 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 NFkappaB and place this cytokine in a strategic role in the local inflammation observed in RA.
Morel
J C
JC
Department of Medicine, Northwestern University Medical School, Chicago, IL 60611, USA.
Park
C C
CC
Kumar
P
P
Koch
A E
AE
D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D019743:Chemokines, CXC / Q000096:biosynthesis*; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D020382:Interleukin-18 / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013583:Synovial Membrane / Q000378:metabolism* / Q000473:pathology
D019743:Chemokines, CXC; D020382:Interleukin-18; D016328:NF-kappa B