Prostaglandin E₂ stimulates adaptive IL-22 production and promotes allergic contact dermatitis.

Abstract

Atopic dermatitis (AD) and allergic contact dermatitis (ACD) are both forms of eczema and are common inflammatory skin diseases with a central role of T cell-derived IL-22 in their pathogenesis. Although prostaglandin (PG) E₂ is known to promote inflammation, little is known about its role in processes related to AD and ACD development, including IL-22 upregulation. We sought to investigate whether PGE₂ has a role in IL-22 induction and development of ACD, which has increased prevalence in patients with AD. T-cell cultures and in vivo sensitization of mice with haptens were used to assess the role of PGE₂ in IL-22 production. The involvement of PGE₂ receptors and their downstream signals was also examined. The effects of PGE₂ were evaluated by using the oxazolone-induced ACD mouse model. The relationship of PGE₂ and IL-22 signaling pathways in skin inflammation were also investigated by using genomic profiling in human lesional AD skin. PGE₂ induces IL-22 from T cells through its receptors, E prostanoid receptor (EP) 2 and EP4, and involves cyclic AMP signaling. Selective deletion of EP4 in T cells prevents hapten-induced IL-22 production in vivo, and limits atopic-like skin inflammation in the oxazolone-induced ACD model. Moreover, both PGE₂ and IL-22 pathway genes were coordinately upregulated in human AD lesional skin but were at less than significant detection levels after corticosteroid or UVB treatments. Our results define a crucial role for PGE₂ in promoting ACD by facilitating IL-22 production from T cells.