Novel Inhibitors of Cytokine-induced IκBα Phosphorylation and Endothelial Cell Adhesion Molecule Expression Show Anti-inflammatory Effects in Vivo

We have identified two compounds that inhibit the expression of endothelial-leukocyte adhesion molecules intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin. These compounds act by inhibiting tumor necrosis factor-α-induced phosphorylation of IκB-α, resulting in decreased nuclear factor-κB and decreased expression of adhesion molecules. The effects on both IκB-α phosphorylation and surface expression of E-selectin were irreversible and occurred at an IC₅₀ of approximately 10 μm. These agents selectively and irreversibly inhibited the tumor necrosis factor-α-inducible phosphorylation of IκB-α without affecting the constitutive IκB-α phosphorylation. Although these compounds exhibited other activities, including stimulation of the stress-activated protein kinases, p38 and JNK-1, and activation of tyrosine phosphorylation of a 130–140-kDa protein, these effects are probably distinct from the effects on adhesion molecule expression since they were reversible. One compound was evaluated <i>in vivo</i> and shown to be a potent anti-inflammatory drug in two animal models of inflammation. The compound reduced edema formation in a dose-dependent manner in the rat carrageenan paw edema assay and reduced paw swelling in a rat adjuvant arthritis model. These studies suggest that inhibitors of cytokine-inducible IκBα phosphorylation exert anti-inflammatory activity <i>in vivo</i>.