A novel role for interleukin-18 in adhesion molecule induction through NF kappa B and phosphatidylinositol (PI) 3-kinase-dependent signal transduction pathways

Interleukin-18 (IL-18) is a novel proinflammatory cytokine found in serum a nd joints of patients with rheumatoid arthritis (RA). We studied a novel ro le for IL-18 in mediating cell adhesion, a vital component of the inflammat ion found in RA and other inflammatory diseases. We examined the expression of cellular cell adhesion molecules E-selectin, vascular cell adhesion mol ecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) on endothe lial cells and RA synovial fibroblasts using flow cytometry. Adhesion of th e monocytelike cell line HL-60 to endothelial cells was determined by immun ofluorescence. IL-18 significantly enhanced ICAM-1 and VCAM-1 expression on endothelial cells and RA synovial fibroblasts. In addition, IL-18 induced E-selectin expression on endothelial cells and promoted the adhesion of HL- 60 cells to IL-18-stimulated endothelial cells. Neutralizing anti-VCAM-1 an d anti-E-selectin could completely inhibit HL-60 adherence to endothelial c ells. IL-18-induced adhesion molecule expression appears to be mediated thr ough nuclear factor kappaB (NF kappaB) and phosphatidyl-inositol 3 kinase ( PI 3-kinase) since addition of inhibitors to either NF kappaB (pyrrolidine dithiocarbamate and N-acetyl-L-cysteine) or PI 3-kinase (LY294002) inhibite d RA synovial fibroblast VCAM-1 expression by 50 to 60%. Addition of both i nhibitors resulted in inhibition of VCAM-1 expression by 85%. In conclusion , the ability of IL-18 to induce adhesion molecule expression on endothelia l cells and IRA synovial fibroblasts indicates that IL-18 may contribute to RA joint inflammation by enhancing the recruitment of leukocytes into the joint. IL-18 requires NF kappaB as well as PI 3-kinase to induce VCAM-1 on RA synovial fibroblasts, suggesting that there may be two distinct pathways in IL-18-induced adhesion molecule expression.