Role of pro‐inflammatory cytokines in the pathophysiology of herpes simplex virus superinfection in Darier’s disease

다국어 초록 (Multilingual Abstract)

Darier’s disease (DD) and Hailey–Hailey disease (HHD), belonging to a hereditary acantholytic dermatosis caused by mutations in ATP2A2 and ATP2C1, respectively, are easily affected by eczema herpeticum (EH) induced by mostly herpes simplex virus (HSV) superinfection. However, the mechanisms by which those patients with DD or HHD are susceptible to HSV are not well elucidated. Here, we experienced two cases with DD, including three episodes of the exacerbation of DD after the development of severe EH. We serially measured serum cytokines before and after the development of EH and DD in these patients. Furthermore, we analyzed the effect of pro‐inflammatory cytokines on the mRNA expression of ATP2A2 and ATP2C1, and HSV growth. The timing of EH onset in these patients was coincident with the increase in serum interleukin (IL)‐6 and tumor necrosis factor (TNF)‐α levels. Moreover, the exacerbation of DD occurred in the non‐lesional skin of EH after EH remission (mean 24 days, ranging 15–30 days after EH onset). IL‐6 and TNF‐α enhanced HSV‐1 growth, and ATP2A2 and ATP2C1 mRNA levels were downregulated by IL‐6 stimulation in cultured differentiated keratinocytes. Increased pro‐inflammatory cytokines IL‐6 and TNF‐α lead to development of severe EH lesions via accentuation of HSV growth. IL‐6 acts as an exacerbating factor of DD and HHD by downregulating the expression of responsible genes.