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    • IL IL E is a member

    2018-10-20

    IL-25 (IL-17E) is a member of the IL-17 family (Iwakura et al., 2011). However, unlike IL-17A or F, the better-known members of this IL family that have direct roles in autoimmune and chronic inflammatory diseases, IL-25 actually appears to protect against IL-17A/Th17 and Th1 states (Caruso et al., 2009a). IL-25-deficient mice, in addition to promoting Th1 responses, have a higher amount of IL-17A-expressing T cells and IFN-γ-expressing T cells in Th17-mediated experimental autoimmune encephalomyelitis (EAE), a model of human multiple sclerosis (Kleinschek et al., 2007). Interestingly, accumulating data demonstrate that IL-25 has another role in the immune system by promoting Th2 responses, preventing helminth infections (Fallon et al., 2006) as well as eosinophilic airway inflammation (Kim et al., 2002). To date, reported sources of IL-25 include immune cells, such as T cells, macrophages, monocyte-derived dendritic cells, mast cells, eosinophils, and basophils, as well as non-immune cells, such as epithelial and endothelial AG-14361 (Monteleone et al., 2010). We found IL-25 to be highly and constitutively expressed by diverse sources of hMSCs, but not fibroblasts. Moreover, our data show that IL-25 is directly responsible for hMSC suppression of allogeneic Th17 responses, including decreasing the highly pathogenic IL-17A/IFN-γ+ cells, further demonstrating that IL-25 is broadly protective against Th17 and Th1 responses. It is interesting to speculate on other possible biological roles of IL-25 in hMSCs given its high constitutive expression. Further studies are ongoing to evaluate whether this cytokine plays a role in hMSC proliferation and/or differentiation. One of the striking findings of this study is that IL-25 directly upregulates the surface molecule PD-L1 in both leukocyte—monocytes—and non-leukocyte populations—hMSCs. PD-L1 is strongly immunosuppressive, being an inhibitor of autologous T cell activation in several autoimmune diseases (Keir et al., 2008), and blockade of its receptor, PD-1, on T cells can be very effective against cancer immunosuppression, as recently demonstrated (Topalian et al., 2012). Recently, a report showed that mouse MSCs suppress Th17 responses through this pathway (Luz-Crawford et al., 2012). However, data in this report showed that blockage of the PD-L1/PD-1 pathway only partially reversed mouse MSC suppression of Th17 responses, implicating other factors in this process. Our data also demonstrate that silencing of PD-L1 results in partial reversal of hMSC suppression of Th17 responses, while silencing of IL-25 results in a significantly higher and nearly complete reversal of hMSC-mediated Th17 suppression (Figure 5D). In addition, the degree of knockdown of PD-L1 expression was similar whether the siRNA specific for IL-25 or PD-L1 was used (Figure 5F). Moreover, we found evidence that IL-25 can directly affect the transcription of PD-L1 in both hMSCs and human leukocytes through STAT3, which helps to resolve the question of PD-L1 transcriptional control (Sumpter and Thomson, 2011; Wölfle et al., 2011). Critically, mouse MSCs do not express PD-L1 in steady state, whereas hMSCs constitutively express a high level of PD-L1 (Stagg et al., 2006). It is important to note that while data from mouse systems are clearly important, in MSC immunobiology, at times the results from mouse and human systems have been conflicting (Eliopoulos et al., 2005; Le Blanc et al., 2008), as was the case with PD-L1 expression. Based on the clinical response to hMSC therapy on various immune-related diseases, it appears that hMSCs exert strong immunomodulatory effects (Le Blanc and Mougiakakos, 2012), which is not always evident with mouse studies (Eliopoulos et al., 2005). Thus, to elucidate mechanisms involved in hMSC therapeutic applications, in vitro studies using hMSCs are still critical to conduct. In summary, our findings demonstrate that hMSCs suppress Th17 responses, which require both the secreted factor IL-25 and IL-25-mediated upregulation of surface PD-L1. The downstream signaling pathways of JNK and STAT3 are involved in IL-25 regulation of PD-L1, with STAT3 implicated in the transcriptional control of PD-L1. In addition to the known roles of Th17 cells in autoimmune and chronic inflammatory diseases, recent studies have shown the importance of Th17 cells in enhancing the efficacy of checkpoint immunotherapy (Lutz et al., 2014). Modulation of IL-25, therefore, may have strong clinical implications since this cytokine can modulate PD-L1/PD-1 interactions and Th17 cells as well. Our findings provide a better understanding of the crosstalk between hMSCs and Th17 cells, as well as highlight the IL-25/STAT3/PD-L1 axis as a candidate therapeutic target for relevant diseases.