The NF-kappa B inhibitor, tepoxalin, suppresses surface expression of the cell adhesion molecules CD62E, CD11b/CD18 and CD106.
Tepoxalin, a dual enzyme inhibitor of cyclooxygenase and 5-lipoxygenase has been shown to inhibit T-cell activation. Its immunosuppressive property is distinct from cyclosporin because only tepoxalin, but not cyclosporin, suppresses NF-kappa B activation. Here we report that tepoxalin selectively inhibits intercellular adhesion molecule-1 (ICAM-1, CD54)/MAC-1 (CD11b/CD18) dependent adhesion of polymorphonuclear cells to IL-1 activated human umbilical vein endothelial cells. The mechanism of inhibition is related to the surface expression of several cell adhesion molecules. Flow cytometry analyses on cultured cells that were treated with tepoxalin or antisense oligonucleotides to the P65/p50 subunit of NF-kappa B, and then stimulated with PMA, revealed a reduced expression of CD11b/CD18 on monocytic HL60 cells, and endothelial adhesion molecule-1 (CD62E) and vascular adhesion molecule-1 (CD106) on human umbilical vein endothelial cells. Expression of other adhesion molecules such as lymphocyte function associated-antigen-1 (CD11a/CD18) and CD54 were unaffected. Tepoxalin also inhibited the secretion of a NF-kappa B regulated chemokine, IL-8, a known inducer of CD11b/CD18 expression. Thus the suppression of CD11b/CD18 expression by tepoxalin may involve IL-8. Our results suggest that by inhibiting NF-kappa B activation, surface expression of several adhesion molecules can be modulated and that tepoxalin may be useful in treating selected adhesion mediated events such as leukocyte migration or atherosclerotic plaque formation.
Lee
D H
DH
R.W. Johnson Pharmaceutical Research Institute, Don Mills, Ontario, Canada. leed@alloy.prius.jnj.com
Tam
S S
SS
Wang
E
E
Taylor
G R
GR
Plante
R K
RK
Lau
C Y
CY
D019138:Antibodies, Blocking / Q000276:immunology; D002448:Cell Adhesion / Q000187:drug effects*; D002478:Cells, Cultured; D019040:E-Selectin / Q000096:biosynthesis*; D004727:Endothelium / Q000166:cytology; D005434:Flow Cytometry; D006801:Humans; D006825:Hybridomas; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis*; D007375:Interleukin-1 / Q000494:pharmacology; D016209:Interleukin-8 / Q000032:analysis / Q000276:immunology / Q000378:metabolism; D008214:Lymphocytes; D016177:Macrophage-1 Antigen / Q000096:biosynthesis*; D016328:NF-kappa B / Q000235:genetics; D009504:Neutrophils; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis*
D019138:Antibodies, Blocking; D019040:E-Selectin; D007166:Immunosuppressive Agents; D007375:Interleukin-1; D016209:Interleukin-8; D016177:Macrophage-1 Antigen; D016328:NF-kappa B; D016376:Oligonucleotides, Antisense; D011720:Pyrazoles; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D013755:Tetradecanoylphorbol Acetate; C073135:tepoxalin