Prostaglandin I(2) analogues enhance already exuberant Th17 cell responses in systemic sclerosis.
OBJECTIVE
Among pleiotropic effects, the capacity of prostaglandin I(2) (PGI(2)) analogues to affect adaptive immunity remains poorly characterised. The purpose of this study was to assess whether PGI(2) 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 PGI(2) analogue effects.


RESULTS
Th17 and Th22 cells were more abundant in individuals with SSc than in HD. PGI(2) 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 PGI(2) 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.
Division of Immunology and Allergy, University Hospital and School of Medicine, Geneva, Switzerland.
Marie-Elise
ME
Truchetet
Yannick
Y
Allanore
Elisa
E
Montanari
Carlo
C
Chizzolini
Nicolò Costantino
NC
Brembilla
D056704:Adaptive Immunity / Q000187:drug effects* / Q000276:immunology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000959:Antihypertensive Agents / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D006801:Humans; D016285:Iloprost / Q000494:pharmacology*; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D053760:Interleukin-23 Subunit p19 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D012595:Scleroderma, Systemic / Q000188:drug therapy* / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D055815:Young Adult; D000097043:Interleukin-22
D000959:Antihypertensive Agents; D017868:Cyclic AMP-Dependent Protein Kinases; D011464:Epoprostenol; D016285:Iloprost; D007371:Interferon-gamma; D020381:Interleukin-17; D053760:Interleukin-23 Subunit p19; D007378:Interleukins; D010975:Platelet Aggregation Inhibitors; D000097043:Interleukin-22; C508717:IL17A protein, human; C508840:IL23A protein, human; C048081:beraprost; C427248:treprostinil