Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.
Iloprost Enhances Th17 and Th22 While Decreasing Th1 Cells Expansion in Healthy and Systemic Sclerosis Mononuclear Cells.
Truchetet1, Marie-Elise, Allanore2, Yannick, Chizzolini1, Carlo, Brembilla1, Nicolò Costantino
In systemic sclerosis (SSc) inappropriate T cell responses are thought to participate in initiating events ultimately leading to excessive extracellular matrix deposition and fibrosis. Iloprost, a prostacyclin analog, is currently used as vasodilating agent to treat SSc-related vascular events. However, its immunomodulatory properties in humans remain unclear. Aim of this work was to assess whether Iloprost may influence the polarization and the cytokine-production capacity of T helper cells in healthy donors (HD) and SSc patients and to identify the receptors mediating its effects.
Peripheral blood mononuclear cells (PBMC) and clinical characteristics were obtained from 30 SSc and 29 age- and sex-matched HD upon informed consent and approval by the ethics committee. None of the patient was under immunosuppressant agents at the time of sampling. Frequencies of interleukin (IL)-17A, IL-22, interferon-gamma (IFN-gamma), and IL-4-producing CD4 T cells were assessed upon 7 days of polyclonal expansion in the presence or absence of Iloprost by multiparametric flow cytometry. The cytokines released in the supernatants were quantified by ELISA. Selective IP and EP receptor antagonists were used to identify the receptors mediating Iloprost effects. Differences between the means were assessed by the Student's t test. P values lower than 0.05 were considered as significant.
Iloprost (Bayer Schering Pharma, Berlin, Germany) enhanced in a dose-dependent manner the CD4+ T cell production of IL-22 and IL-17A while decreasing the production of IFN-gamma. Analysis at single cell level confirmed these results and revealed that Iloprost treatment in vitro slightly but significantly favored the expansion of Th17 (P<0.0001) and Th22 cells (P<0.0001). Simultaneously, Iloprost induced a quantitatively more important decrease in Th1 cells (P<0.0001). No effects of Iloprost were observed on Th2 cells producing IL-4. Of interest, PBMC from SSc and HD responded to the same extent to Iloprost. Finally preliminary experiments indicated that the decreased production of IFN-gamma in the presence of iloprost was specifically reversed by CAY10449 (Cayman Chemical Co, Ann Arbor, MI), a peptide inhibitor specific for IP, while the enhanced production of IL-17A and IL-22 was partially inhibited by CAY10449, AH6809 (antagonist of EP1, EP2, and EP3), and AH23848 (antagonist of EP4) suggesting that the effect of Iloprost on cytokine production by PBMC was cooperatively mediated by several distinct receptors.
Our results show that Iloprost in vitro increases IL-17A and IL-22 while decreasing IFN-gamma production by CD4+ T cells, underlying new immunomodulatory proprieties of this compound distinct from its action on endothelial cells and fibroblasts. The capacity of Iloprost to modulate the production of cytokines by T cells should be taken into account in current Iloprost-based therapies and could be exploited for novel therapeutic approaches.
To cite this abstract, please use the following information:
Truchetet, Marie-Elise, Allanore, Yannick, Chizzolini, Carlo, Brembilla, Nicolò Costantino; Iloprost Enhances Th17 and Th22 While Decreasing Th1 Cells Expansion in Healthy and Systemic Sclerosis Mononuclear Cells. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :712