Mutual upregulation of endothelin‐1 and IL‐25 in atopic dermatitis

Abstract Background Endothelin‐1 ( ET ‐1) has been reported to evoke histamine‐independent pruritus in mammals. However, its association with pruritus or inflammation of atopic dermatitis ( AD ) has not been clarified. We sought to investigate the role of ET ‐1 in the skin inflammation of AD . Methods To examine the role of ET ‐1 in AD , we investigated the expression of ET ‐1 and IL ‐25 in the skin of an AD mouse model and patients with AD and examined the mutual regulatory relationship between ET ‐1 and IL ‐25, one of the important cytokines in AD , using the human HaCaT keratinocyte cell line. Results We immunohistochemically confirmed the upregulation of ET ‐1 and IL ‐25 expression in the epidermis of both the AD mouse model and patients with AD . In vitro , IL ‐25 upregulated ET ‐1 mRNA and protein expression in a concentration‐ and time‐dependent fashion in HaCaT cells. This IL ‐25‐induced ET ‐1 expression was inhibited by ERK 1/2 or JNK inhibitor. In a reciprocal manner, ET ‐1 also induced IL ‐25 upregulation. The enhancing effect of ET ‐1 on IL ‐25 was inhibited by an endothelin A receptor antagonist, ERK 1/2 inhibitor, or p38 inhibitor, but not by an endothelin B receptor antagonist or JNK inhibitor. Conclusion These findings suggest that mutual upregulation of ET ‐1 and IL ‐25 takes place in the epidermis of AD , which may be a future target for antipruritic agents.