NOVEL INHIBITORS OF CYTOKINE-INDUCED I-KAPPA-B-ALPHA PHOSPHORYLATION AND ENDOTHELIAL-CELL ADHESION MOLECULE EXPRESSION SHOW ANTIINFLAMMATORY EFFECTS IN-VIVO

We have identified two compounds that inhibit the expression of endoth elial-leukocyte adhesion molecules intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin, These compounds act by inhibiting tumor necrosis factor-alpha-induced phosphorylation of I kappa B-alpha, resulting in decreased nuclear factor-kappa B and dec reased expression of adhesion molecules, The effects on both I kappa B -alpha phosphorylation and surface expression of E-selectin were irrev ersible and occurred at an IC50 of approximately 10 mu M. These agents selectively and irreversibly inhibited the tumor necrosis factor-alph a-inducible phosphorylation of I kappa B-alpha without affecting the c onstitutive I kappa B-alpha Phosphorylation. Although these compounds exhibited other activities, including stimulation of the stress-activa ted protein kinases, p38 and JNK-1, and activation of tyrosine phospho rylation of a 130-140-kDa protein, these effects are probably distinct from the effects on adhesion molecule expression since they were reve rsible, One compound was evaluated in vivo and shown to be a potent an ti-inflammatory drug in two animal models of inflammation, The compoun d reduced edema formation in a dose-dependent manner in the rat carrag eenan paw edema assay and reduced pam swelling in a rat adjuvant arthr itis model, These studies suggest that inhibitors of cytokine-inducibl e I kappa B alpha phosphorylation exert anti-inflammatory activity in vivo.