Calum T Robb1, Henry J McSorley1, Jinju Lee2, Tomohiro Aoki2, Cunjing Yu1, Siobhan Crittenden1, Anne Astier1, Jennifer M Felton1, Nicholas Parkinson1, Adane Ayele3, Richard M Breyer4, Stephen M Anderton1, Shuh Narumiya2, Adriano G Rossi1, Sarah E Howie1, Emma Guttman-Yassky5, Richard B Weller1, Chengcan Yao6. 1. Medical Research Council (MRC) Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom. 2. Center for Innovation in Immunoregulative Technology and Therapeutics (AK Project), Kyoto University Graduate School of Medicine, Kyoto, Japan; Core Research for Evolutional Science and Technology, Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan. 3. Department of Dermatovenereology, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia. 4. Department of Veterans Affairs, Tennessee Valley Health Authority, Nashville, Tenn; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn. 5. Department of Dermatology and the Laboratory for Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, NY; Laboratory for Investigative Dermatology, Rockefeller University, New York, NY. 6. Medical Research Council (MRC) Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom. Electronic address: Chengcan.Yao@ed.ac.uk.
Abstract
BACKGROUND: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Our results define a crucial role for PGE2 in promoting ACD by facilitating IL-22 production from T cells.
BACKGROUND: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Our results define a crucial role for PGE2 in promoting ACD by facilitating IL-22 production from T cells.
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