Objective Among pleiotropic effects, the capacity of prostaglandin I2 (PGI2) analogues to affect adaptive immunity remains poorly characterised. The purpose of this study was to assess whether PGI2 analogues could affect T helper (Th) cell responses in patients with systemic sclerosis (SSc) and healthy donors (HD).
Methods Peripheral blood mononuclear cells (PBMC) were obtained from 33 patients with SSc and 29 HD. Cytokine levels in PBMC and monocyte/CD4 T cell cultures were quantified by immunoassays. The frequencies of interleukin (IL)-17A, IL-22, interferon γ (IFNγ) and IL-4-producing CD4 T cells were assessed by multiparametric flow cytometry. Selective receptor antagonists, cytokine blocking antibodies and signalling protein inhibitors were used to identify the receptors and signalling pathways mediating PGI2 analogue effects.
Results Th17 and Th22 cells were more abundant in individuals with SSc than in HD. PGI2 analogues (iloprost, treprostinil and beraprost) significantly increased IL-17A and IL-22 in vitro while decreasing IFNγ production both in SSc and HD PBMC. These effects relied on the specific expansion of Th17 and Th22 and inhibition of Th1 cells. The enhanced Th17 cell responses depended on increased IL-23 production by monocytes, involved the IP prostacyclin receptor and required protein kinase A activation. Importantly, in vivo administration of iloprost in individuals with SSc presenting with digital ulcers resulted in a significant increase in the frequency of Th17 cells.
Conclusions These findings demonstrate that PGI2 analogues affect Th cell differentiation/expansion programmes, favouring Th17 and inhibiting Th1 cell responses in SSc. The impact of these changes on the disease course needs to be taken into consideration and further exploited to improve SSc.
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Funding This work was supported in part by grant 31003A_124941/1 from the Swiss National Science Foundation, the Association des Sclérodermiques de France and the Groupe français de recherche sur la sclérodermie to CC. MET was supported in part by a grant from the Société Française de Rhumatologie, France. EM was supported by a grant from the Manodori Foundation, Reggio Emilia, Italy.
Ethical approval Ethical approval was obtained from the Comité de Protection des personnes Ile de France.
Provenance and peer review Not commissioned; externally peer reviewed.
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