Prostaglandin E2 Stimulates Adaptive IL-22 Production and Promotes Allergic Contact Dermatitis

[Speaker] Calum T Robb:1
[Co-author] Jinju Lee:2, Jennifer M Felton:1, Shuh Narumiya:2, Adriano G Rossi:1, Sarah E Howie:1, Chengcan Yao:1
1:Queens Medical Research Institute, University of Edinburgh, Scotland, UK, 2:Department of Drug Discovery Medicine, Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan

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 E2 (PGE2) is known to promote inflammation, little is known about its role in processes related to AD and ACD development, including IL-22 upregulation.

We set out to investigate whether PGE2 has a role in T cell-derived IL-22 induction and development of ACD, which has augmented prevalence in patients with AD.

T cell cultures and in vivo sensitization of mice with powerful haptens (oxazolone and dinitrofluorobenzene) 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 specific effects of PGE2 during ACD pathogenesis were evaluated by using the oxazolone-induced ACD mouse model. Gene expression of PGE2 and IL-22 signaling pathways was also investigated by using genomic profiling in human lesional AD skin biopsies.

PGE2 promotes IL-22 production from T cells through its receptors, E prostanoid receptor 2 (EP2) and EP4. This is mediated by its downstream cAMP-PKA signaling and probably involves the transcription factor aryl hydrocarbon receptor (AHR). Selective deletion of EP4 in T cells prevents hapten-induced adaptive IL-22 production in vivo. Importantly, blockade of endogenous PGE2 production by a COX inhibitor indomethacin or deletion of EP4 in T cells limit atopic-like skin inflammation in the oxazolone-induced mouse ACD model. Moreover, both PGE2 and IL-22 pathway genes were coequally upregulated in human AD lesional skin but were down-regulated after treatment with betamethasone or ultraviolet B (UVB) radiation, both common therapies for AD.

Our results thus define a crucial role for PGE2 in promoting ACD by facilitating T cell-derived IL-22 production.
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