Interleukin-17 enhances immunosuppression by mesenchymal stem cells

Abstract

IL-17 is one of the most potent and most actively investigated proinflammatory cytokines. In this study, we examined the effect of IL-17 on mesenchymal stem cells (MSCs) under the influence of inflammatory cytokines. Ironically, IL-17 dramatically enhanced the immunosuppressive effect of MSCs induced by IFNγ and TNFα, revealing a novel role of IL-17 in immunosuppression. Interestingly, we found that this action of IL-17 was dependent on the promoted expression of a key immune suppressive molecule, inducible nitric oxide synthase (iNOS), in MSCs. In a concanavalin A (ConA)-induced hepatitis mouse model, we found that IL-17 also enhanced the in vivo immunosuppressive effect of MSCs in an iNOS-dependent manner. Moreover, this promoting effect of IL-17 was found to be exerted through enhancing mRNA stability by modulating the protein level of ARE/poly(U)-binding/degradation factor 1 (AUF1), a well-known factor that promotes mRNA decay. In auf1−/− MSCs, IFNγ and TNFα could induce maximal immunosuppressive effect, both in vitro and in vivo, without the need for IL-17. Thus, our studies demonstrated that in the presence of MSCs, IL-17 promotes immunosuppression.

Type I interferons exert anti-tumor effect via reversing immunosuppression mediated by mesenchymal stromal cells

“…Our previous studies showed that NO and chemokines are key factors for the immunosuppressive effect of mouse MSCs. The amount of NO is critical for the immunosuppressive capacity of MSCs (8, 15). Immunosuppressive capabilities of tumor- infiltrated MSCs counteract anti-tumor immunity within the tumor microenvironment and thus promote tumor growth (12).…”

Mesenchymal stem cells and adaptive immune responses

“…In fact, it has been reported that pretreating MSCs with IFN- significantly improved the therapeutic effects of MSCs in animal models of colitis and GvHD [45,82]. Especially, when IL-17 is included in the pretreatment cytokine 'cocktail', MSCs have better therapeutic effects on ConA-induced mouse hepatitis [80]. These improvements are likely attributed, at least in part, to the enhancement of immunosuppressive activity of MSCs induced by pro-inflammatory cytokines.…”

“…presence of IL-17 dramatically enhanced the immunosuppressive function of MSCs induced by IFN- and TNF-in both in vitro and in vivo studies[80]. The promoting effect of IL-17 was found to be exerted through enhancing iNOS mRNA stability by modulating AUF1.…”

The roles of immune cells in bone healing; what we know, do not know and future perspectives

“…Together with IFN-g and TNF-a, MSCs that are activated by IL-1 can perform immunosuppressive functions associated with the production of prostaglandin 2 (PGE2) and IL-8 [46]. Furthermore, it has been shown that IL-17 is another licensing cytokine that can enhance the immunosuppressive functions of MSCs both in vivo and in vitro [47]. In summary, multiple licensing cytokines help to programme MSCs towards immunosuppressive activity in order to control the inflammatory phase of healing.…”