The Effects of Cannabinoid Agonist, Heat Shock Protein 90 and Nitric Oxide Synthase Inhibitors on Increasing IL-13 and IL-31 Levels in Chronic Pruritus

Abstract

ABSTRACT Background Heat shock protein 90 (Hsp90) inhibitor and cannabinoid agonists ameliorate dry skin-induced chronic itch. We have recently reported that cannabinoids, hsp90 and nitric oxide (NO) are involved in dry skin-induced itch. Here, we investigated the contribution of the Th2 cell signaling pathway to the antipruritic effect of the hsp90 inhibitor 17-Alilamino-17-demethoxygeldanamycin (17-AAG), nitric oxide synthase (NOS) inhibitor Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME) and cannabinoid agonist WIN 55,212–2 on a dry skin-induced scratch. Methods Dry skin-induced chronic itching was created by topical application of AEW (acetone/diethyl ether/water). WIN 55,212–2 (1 mg/kg, i.p.), L-NAME (1 mg/kg, i.p.) and increasing doses of 17-AAG (1, 3 and 5 mg/kg,i.p.) were administered to Balb/c mice (for each group, n = 6). After these applications, skin tissues were taken from the nape region of all of the mice. Gene and protein expressions of IL-13 and IL-31 were evaluated in skin tissues by RT-PCR and immunohistochemistry, respectively. Results IL-13 and IL-31 mRNA expressions and immune positive cell counts were increased in the AEW applied groups. WIN 55,212–2 reduced both of the increased cytokines levels, while L-NAME decreased only the IL-13. 17-AAG dose-dependently reduced the increased cytokine levels. IL-13 and IL-31 levels significantly decreased following the co-administration of these agents. Conclusion These results show that increased levels of IL-13 and IL-31 are associated with pruritus. Hsp90 inhibition and cannabinoid system activation may induce antipruritic effects through down-regulation of these cytokines.