The present study also showed that EP deficiency
The present study also showed that EP2 deficiency and EP4 antagonism significantly suppressed psoriatic 4EGI-1 in an imiquimod model. Notably, however, the combined EP2 deficiency and EP4 antagonism did not completely suppress ear swelling in this model, possibly because there is the IL-17–independent component in skin inflammation in this model. In this study we also tested the effect of COX inhibitors in an IL-23–induced psoriasis model and found that COX inhibitors are as potent as EP2 and EP4 antagonists in suppressing psoriasis-like skin inflammation in this model. The question is whether COX inhibitors are beneficial in TH17-driven human autoimmune diseases. COX inhibitors, particularly celecoxib, are used for treatment of the early stage of rheumatoid arthritis and in patients with mild psoriatic arthritis. In these cases COX inhibitors produce good symptomatic relief. Although this effect is ascribed to their analgesic and general anti-inflammatory actions, our study suggests that it might be derived at least in part from their suppressive action on TH17-mediated pathology, a possibility that should be tested in the future. On the other hand, COX inhibitors have less appreciable therapeutic benefits in patients with established psoriasis and advanced rheumatoid arthritis in human patients. There are several plausible reasons. A PG-mediated process might be critical in triggering pathogenic TH17 cell generation but not so in advanced stage of diseases that might be regulated dominantly by established TH17 cells. Another reason might be the fact that PGs cause immune inflammation not by acting alone but by working with cytokines and boosting and modifying their actions. Therefore, COX inhibitors might exert therapeutic benefits more effectively when combined with anticytokine drugs and lessen the dose of the latter. Finally, COX inhibitors might divert arachidonate metabolism to leukotriene. Recent studies suggest that leukotrienes facilitate maturation and migration of TH17 cells.70, 71 Further studies need to be conducted to unravel these issues. Another topic to be discussed on use of PGE2 in patients with psoriasis is its facilitative action in UV irradiation therapy, which at a glance contradicts our present findings on the facilitative action of PGE2 on TH17 pathogenicity. UVB irradiation is an effective therapeutic treatment of psoriasis by inducing immunosuppression. We previously showed that UVB induces PGE2 in the epidermis and PGE2-EP4 signaling mediates systemic immunosuppression through upregulation of receptor activator of NF-κB ligand in keratinocytes and inducing regulatory T cells. Thus the PGE2-EP4 signaling in this case facilitates immunosuppression and not immune activation. One point is that UVB does not penetrate to the dermis and the events it causes are within the epidermis, whereas IL-23–induced inflammatory events occur in the dermis. Another point is a difference in context, UVB irradiation in the UV therapy and IL-23 in psoriatic inflammation. PGE2 alone does not induce either effect but functions directionally dependent on the context. Finally, we examined the relevance of our findings to human disease by analyzing biopsy samples from patients with psoriasis. Psoriatic lesional skin overexpressed not only TH17 signature genes, including IL23A, IL12B, IL23R, IL17A, IL17F, IL22, STAT3, and NFKB1, but also those involved in PGE2 biosynthesis and function, such as PTGS2, PTGES, PTGES2, and PTGER4. Expression of TH17 signature genes shows positive correlation with PTGES, PTGES2, and PTGER4 and negative correlation with HPGD and the anti–IL-23 therapy downregulated expression of not only genes in the IL-23/IL-17 pathway (eg, IL23A, IL23R, and IL17A) but also those in PGE2 synthesis, suggesting that these 2 are functionally linked. These findings together with the finding by Kofler et al that EP2 is expressed in TH17 cells from patients with multiple sclerosis and that forced expression of EP2 in healthy TH17 cells triggers expression of pathogenic genes indicate that T cell–intrinsic EP2/EP4 signaling is critical in IL-23–driven TH17 cell pathogenesis also in human subjects and support a view that the combined inhibition of EP2 and EP4 is of value in therapeutic intervention of various TH17-mediated diseases.