Novel Inhibitors of Cytokine-induced IκBα Phosphorylation and Endothelial Cell Adhesion Molecule Expression Show Anti-inflammatory Effects in Vivo
1997; Elsevier BV; Volume: 272; Issue: 34 Linguagem: Inglês
10.1074/jbc.272.34.21096
ISSN1083-351X
AutoresJacqueline W. Pierce, Robert Schoenleber, Gary Jesmok, Jennifer L. Best, Sarah A. Moore, Tucker Collins, Mary E. Gerritsen,
Tópico(s)Immune Response and Inflammation
ResumoWe 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 IC 50 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 in vivo 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 in vivo .
Referência(s)