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 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 kappa B (NF kappa B) and phosphatidyl-inositol 3 kinase (PI 3-kinase) since addition of inhibitors to either NF kappa B (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 NF kappa B 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.
Morel
J C
JC
Northwestern University Medical School, Department of Medicine, Chicago, Illinois, 60611, USA.
Park
C C
CC
Woods
J M
JM
Koch
A E
AE
D000111:Acetylcysteine / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D019040:E-Selectin / Q000276:immunology / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D020382:Interleukin-18 / Q000494:pharmacology*; D016328:NF-kappa B / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011759:Pyrrolidines / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D013582:Synovial Fluid / Q000187:drug effects / Q000378:metabolism; D013859:Thiocarbamates / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000276:immunology / Q000378:metabolism
D000111:Acetylcysteine; D000911:Antibodies, Monoclonal; D000975:Antioxidants; D019040:E-Selectin; D018799:Intercellular Adhesion Molecule-1; D020382:Interleukin-18; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011759:Pyrrolidines; D013859:Thiocarbamates; D019010:Vascular Cell Adhesion Molecule-1; C020972:pyrrolidine dithiocarbamic acid