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

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  • Robb Calum T
    Queens Medical Research Institute, University of Edinburgh, Scotland, UK
  • Lee Jinju
    Department of Drug Discovery Medicine, Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
  • Felton Jennifer M
    Queens Medical Research Institute, University of Edinburgh, Scotland, UK
  • Narumiya Shuh
    Department of Drug Discovery Medicine, Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
  • Rossi Adriano G
    Queens Medical Research Institute, University of Edinburgh, Scotland, UK
  • Howie Sarah E
    Queens Medical Research Institute, University of Edinburgh, Scotland, UK
  • Yao Chengcan
    Queens Medical Research Institute, University of Edinburgh, Scotland, UK

Description

<p>BACKGROUND</p><p>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.</p><p>OBJECTIVES</p><p>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.</p><p>METHODS</p><p>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.</p><p>RESULTS</p><p>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.</p><p>CONCLUSIONS</p><p>Our results thus define a crucial role for PGE2 in promoting ACD by facilitating T cell-derived IL-22 production.</p>

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