Journal of Biological Chemistry
Volume 276, Issue 40, 5 October 2001, Pages 37069-37075
Journal home page for Journal of Biological Chemistry

MECHANISMS OF SIGNAL TRANSDUCTION
A Novel Role for Interleukin-18 in Adhesion Molecule Induction through NFκB and Phosphatidylinositol (PI) 3-Kinase-dependent Signal Transduction Pathways*

https://doi.org/10.1074/jbc.M103574200Get rights and content
Under a Creative Commons license
open access

Interleukin-18 (IL-18) is a novel proinflammatory cytokine found in serum and joints of patients with rheumatoid arthritis (RA). We studied a novel role for IL-18 in mediating cell adhesion, a vital component of the inflammation found in RA and other inflammatory diseases. We examined the expression of cellular cell adhesion molecules E-selectin, vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) on endothelial cells and RA synovial fibroblasts using flow cytometry. Adhesion of the monocyte-like cell line HL-60 to endothelial cells was determined by immunofluorescence. 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 and anti-E-selectin could completely inhibit HL-60 adherence to endothelial cells. IL-18-induced adhesion molecule expression appears to be mediated through nuclear factor κB (NFκB) and phosphatidyl-inositol 3 kinase (PI 3-kinase) since addition of inhibitors to either NFκB (pyrrolidine dithiocarbamate and N-acetyl-l-cysteine) or PI 3-kinase (LY294002) inhibited RA synovial fibroblast VCAM-1 expression by 50 to 60%. Addition of both inhibitors resulted in inhibition of VCAM-1 expression by 85%. In conclusion, the ability of IL-18 to induce adhesion molecule expression on endothelial cells and RA synovial fibroblasts indicates that IL-18 may contribute to RA joint inflammation by enhancing the recruitment of leukocytes into the joint. IL-18 requires NFκB 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.

Cited by (0)

Published, JBC Papers in Press, July 27, 2001, DOI 10.1074/jbc.M103574200

*

This work was supported by the Gallagher Professorship for Arthritis Research and funds from the Veterans Affairs Research Service. Additional support included funds from National Institutes of Health Grants AI-40987 and HL-58695 and a grant from the French non profit organization groupe d'études et de recherches immuno-rhumatologiques (GERIR).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.