Although it was shown that
Although it was shown that IL-23 signaling induces expression of T17 pathogenic signature genes through activation of STAT3,, transcription factors other than STAT3 are also implicated for induction of pathogenic T17 cells because IL-6, which activates STAT3 similarly to IL-23, cannot induce IL-23R gene expression. Therefore, the identity of additional transcriptional factors and regulatory mechanisms are important issues to be defined. Moreover, how IL-23 cooperates with other inflammatory factors formed in the disease microenvironment and the importance of such cooperation for pathogenic conversion of T17 cells and overall pathology remain largely obscure. Clarification of these points could provide a new opportunity to develop small-molecule drugs as therapeutic alternatives to anti–IL-23 antibodies without systemic immune suppression. Biological agents might additionally cause unpredictable adverse events and can be costly on long-term use. It should also be mentioned that JAK inhibitors that are now being evaluated for their efficacy in patients with autoimmune diseases are presumably not free from adverse effects either because of their effects on general immune suppression.
Prostanoids, including prostaglandin (PG) D, PGE, PGF, PGI, and thromboxane A, are oxygenated metabolites of arachidonic NVP-CGM097 produced by sequential actions of COX and respective synthases and act on their cognate receptors, DP for PGD, EP1 to 4 for PGE, IP for PGI, FP for PGF, and TP for thromboxane A, to exert their actions. Although prostanoids were regarded previously as immunosuppressants,, recent studies have revealed their immunostimulatory actions in processes such as cytokine production, dendritic cell maturation, macrophage activation, and differentiation and expansion of T cell subsets., , Indeed, PGE-EP2 and EP4 (EP2/EP4) signaling enhances T1 differentiation by inducing expression of the IL-12R subunit and the IFN-γ receptor , thus facilitating IL-12 signaling and T1 differentiation., Notably, this PGE-EP2/EP4 signaling was also reported to synergize with IL-23 to facilitate T17 cell expansion both in murine and human T cells., , However, whether and how PGE-EP2/EP4 signaling is involved in induction of pathogenic T17 cells remain unknown.
In this study we have examined how PGE-EP2/EP4 signaling and IL-23 stimulation together regulate the generation of pathogenic T17 cells. Through this analysis, we have identified the transcription mechanisms in addition to STAT3 that regulate expression and T17 pathogenicity. We have further clarified the importance of PGE signaling in T17-mediated immune inflammation and found a correlation between PGE-EP2/EP4 signaling and IL-23–IL-23R signaling in biopsy samples from patients with psoriasis.
Discussion IL-23–IL-23R signaling plays a critical role in generation of pathogenic TH17 cells in autoimmunity.5, 6, 7, 8, 9 However, there remain several issues to be solved on this action: How does this signaling get promoted. What transcriptional mechanisms other than STAT3 are involved? What, along with IL-23 signaling, makes TH17 cells pathogenic? Does such a mechanism operate in vivo and, if so, how much? How relevant are the findings obtained in mice to human subjects? Given the previously reported action of PGE2 on TH17 expansion,43, 44, 45 we focused here on PGE2 action in TH17 pathogenicity to address these issues. We first found that PGE2 synergizes with IL-23 and enhances Il23r expression through EP2 and EP4, a finding consistent with findings in human TH17 cells. We then found that IL-23 stimulation induces PGE2 production in TH17 cells and that IL-23–induced Il23r expression was attenuated by treatment of cells with indomethacin or EP2/EP4 antagonists. Thus, these results suggest a previously unsuspected intrinsic amplification mechanism mediated by PGE2-EP2/EP4 signaling in TH17 cells that helps trigger the initial IL-23 response in premature TH17 cells.