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 Th22-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 up-regulation.
Objectives
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 production of IL-22. The involvement of PGE2 receptors and their downstream signals were also examined. The effects of PGE2 were evaluated using the oxazolone (OXA)-induced ACD mouse model. The relationship of PGE2 and IL-22 signaling pathways in skin inflammation were also investigated using genomic profiling in human lesional AD skin.
Results
PGE2 induces IL-22 from T cells through its receptors EP2 and EP4 and involves cyclic adenosine monophosphate (cAMP) signaling. Selective deletion of EP4 in T-cells prevents hapten-induced IL-22 production in vivo, and inhibition of PGE2 synthesis limits atopic-like skin inflammation in the OXA-induced ACD model. Moreover, both PGE2 and IL-22 pathway genes were coordinately up-regulated in human AD lesional skin, but were below significant detection levels after corticosteroid or ultraviolet band B (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 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. OBJECTIVES 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. METHODS 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. RESULTS 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. CONCLUSIONS Our results thus define a crucial role for PGE2 in promoting ACD by facilitating T cell-derived IL-22 production.
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