NOVEL INHIBITORS OF CYTOKINE-INDUCED I-KAPPA-B-ALPHA PHOSPHORYLATION AND ENDOTHELIAL-CELL ADHESION MOLECULE EXPRESSION SHOW ANTIINFLAMMATORY EFFECTS IN-VIVO
Jw. Pierce et al., NOVEL INHIBITORS OF CYTOKINE-INDUCED I-KAPPA-B-ALPHA PHOSPHORYLATION AND ENDOTHELIAL-CELL ADHESION MOLECULE EXPRESSION SHOW ANTIINFLAMMATORY EFFECTS IN-VIVO, The Journal of biological chemistry, 272(34), 1997, pp. 21096-21103
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.