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

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.

GRAPHICAL ABSTRACT

short-legendThe experimental procedure and hsp90 inhibitor and cannabinoid agonist effects on chronic itch. AEW: aceton/ether/water; 17-AAG:17-Alilamino-17-demethoxygeldanamycin, hsp90 inhibitor; WIN 55,212-2: non-selective cannabinoid receptor agonist; L-NAME: nitric oxide synthase inhibitor Nω-Nitro-L-arginine methyl ester hydrochloride; Th2: T helper 2. (Created withBiorender.Com).

KEYWORDS:

• Cannabinoid
• chronic itch
• hsp90
• IL-13
• IL-31

Author contributions

Z.G.T.S. and S.O. designed the study. Z.G.T.S., A.C.G and R.O. performed the experiments. Z.G.T.S., A.C.G, R.O. and S.O. analysed and interpreted the data. Z.G.T.S. and S.O. wrote the orginal draft and edited the manuscript. All of the authors approved the final version of the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Statement of ethics

The Istanbul University Animal Experiments Local Ethics Committee confirmed all of the animal experimental procedures for this research (Decision No: 02/07/2020–74833).

Additional information

Funding

This study was funded by the Scientific Research Projects Coordination Unit of Istanbul University-Cerrahpasa [Project number:35238].