Geldanamycin, an inhibitor of heat shock protein 90 (Hsp90) mediated signal transduction has anti-inflammatory effects and interacts with glucocorticoid receptor in vivo

1 Histamine, vascular endothelial growth factor, acetylcholine, oestrogen a s well as fluid shear stress activates a mechanism that recruits heat shock protein 90 to the endothelial nitric oxide synthase. The interaction betwe en Hsp90 and eNOS enhances the activation of the enzyme in cells and in int act blood vessels leading to NO production. 2 Intraplantar administration of carrageenan (50 mu l paw(-1)) to mice caus es an oedema lasting 72 h. Geldanamycin (0.1, 0.3, 1 mg kg(-1)), a specific inhibitor of Hsp-90, that inhibits endothelium-dependent relaxations of th e rat aorta, mesentery and middle artery inhibits carrageenan-induced mouse paw oedema in a dose dependent manner. 3 Co-administration to mice of dexamethasone (1 mg kg-l) with geldanamycin (0.3 mg kg(-1)) at anti-inflammatory dose causes a loss of the total anti-i nflammatory effect of each agent alone. 4 RU 486 (10 mg kg(-1)), a well known glucocorticoid receptorial antagonist , does not inhibit oedema formation but prevents the anti-inflammatory acti on of dexamethasone (1 mg kg(-1)). Similarly, RU 386 prevents the anti-infl ammatory action of geldanamycin (0.3 mg kg(-1)). 5 In conclusion we have described for the first time that geldanamycin, an inhibitor of Hsp90 dependent signal transduction, is anti-inflammatory in v ivo implying that Hsp90 is critical for pathways involved in carrageenan-in duced paw oedema. In addition the ability of GA to block NO release and red uce oedema formation suggests a therapeutic rationale for specific inhibito rs of Hsp90 as potential anti-inflammatory drugs.