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

Abstract

Histamine, vascular endothelial growth factor, acetylcholine, oestrogen as well as fluid shear stress activates a mechanism that recruits heat shock protein 90 to the endothelial nitric oxide synthase. The interaction between Hsp90 and eNOS enhances the activation of the enzyme in cells and in intact blood vessels leading to NO production. Intraplantar administration of carrageenan (50 microl paw(-1)) to mice causes 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 the rat aorta, mesentery and middle artery inhibits carrageenan-induced mouse paw oedema in a dose dependent manner. Co-administration to mice of dexamethasone (1 mg kg(-1)) with geldanamycin (0.3 mg kg(-1)) at anti-inflammatory dose causes a loss of the total anti-inflammatory effect of each agent alone. RU 486 (10 mg kg(-1)), a well known glucocorticoid receptorial antagonist, does not inhibit oedema formation but prevents the anti-inflammatory action of dexamethasone (1 mg kg(-1)). Similarly, RU 486 prevents the anti-inflammatory action of geldanamycin (0.3 mg kg(-1)). In conclusion we have described for the first time that geldanamycin, an inhibitor of Hsp90 dependent signal transduction, is anti-inflammatory in vivo implying that Hsp90 is critical for pathways involved in carrageenan-induced paw oedema. In addition the ability of GA to block NO release and reduce oedema formation suggests a therapeutic rationale for specific inhibitors of Hsp90 as potential anti-inflammatory drugs.

Figure 1

(a) Systemic administration of geldanamycin at 0, 24 and 48 h at the dose of 0.1, 0.3 and 1 mg Kg⁻¹ ip inhibits mouse paw oedema development. (b) Dexamethasone at the dose of 0.1 and 1 mg kg sc⁻¹ administered at 0, 24 and 48 h inhibits mouse paw oedema. Basal paw volume was 0.2±0.025 ml. Data are expressed as mean±s.e.mean (n=7) of the increase in paw volume calculates as described in the Methods section. ^**P<0.01; ^***P<0.001 versus control.

Figure 2

(a) Simultaneous administration of geldanamycin (0.3 mg kg⁻¹ ip) and dexamethasone (0.1 mg kg⁻¹) reduces the total anti-inflammatory effect. (b) Simultaneous administration of an higher dose of GA (1 mg kg⁻¹) and dexamethasone (0.1 mg kg⁻¹) does not reduce the total anti-inflammatory effect. ^*P<0.01.

Figure 3

(a) The GR antagonist RU 486 10 mg kg⁻¹ ip reverts dexamethasone (1 mg kg⁻¹ sc) anti-inflammatory effect. (b) The GR antagonist RU 486 10 mg kg⁻¹ ip reverts geldanamycin (0.3 mg kg⁻¹) anti-inflammatory effect. ^**P<0.01; ^***P<0.001 versus control; #P<0.05; ##P<0.01; ###P<0.001 versus DEX treatment (a) or versus GA treatment (b).