A proteasome inhibitor, an antioxidant, or a salicylate, but not a glucocorticoid, blocks constitutive and cytokine-inducible expression of P-selectin in human endothelial cells.

Proteasome inhibitors, antioxidants, salicylates, or glucocorticoids block the cytokine-induced expression of the endothelial cell adhesion molecules E-selectin, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1. These pharmacological agents have been assumed to inhibit the expression of adhesion molecules primarily by blocking activation of the transcription factor NF-kappaB. We found that the proteasome inhibitor ALLN, the antioxidant PDTC, or sodium salicylate, but not the glucocorticoid dexamethasone, inhibited both the constitutive and the interleukin-4- or oncostatin M-induced expression of the adhesion molecule P-selectin in human endothelial cells. ALLN, PDTC, or sodium salicylate decreased P-selectin expression without a detectable requirement for inhibition of NF-kappaB activation or for an intact kappaB element in the P-selectin gene. These results extend the potential anti-inflammatory utility of such drugs to inhibition of P-selectin expression and suggest that they have important actions that do not involve the NF-kappaB system.