Prostaglandin I(2) (PGI(2)) analog is regarded as a potential candidate for 
treating asthma. Human myeloid dendritic cells (mDCs) play a critical role in 
the pathogenesis of asthma. However, the effects of PGI(2) analog on human mDCs 
are unknown. In the present study, circulating mDCs were isolated from six 
healthy subjects. The effects of PGI(2) analogs iloprost and treprostinil on 
cytokine production, maturation and T-cell stimulatory function of human mDCs 
were investigated. Tumor necrosis factor (TNF)-α and interleukin (IL)-10 were 
measured by enzyme-linked immunosorbent assay. The expression of costimulatory 
molecules was investigated by flow cytometry. T-cell stimulatory function was 
investigated by measuring interferon (IFN)-γ, IL-13 and IL-10 production by T 
cells cocultured with iloprost-treated mDCs. Intracellular signaling was 
investigated by Western blot and chromatin immunoprecipitation. We found that 
iloprost and treprostinil induced IL-10, but suppressed TNF-α production in 
polyinosinic-polycytidylic acid (poly I:C)-stimulated mDCs. This effect was 
reversed by the I-prostanoid (IP), E-prostanoid (EP) receptor antagonists or 
intracellular free calcium (Ca(2+)) chelator. Forskolin, an adenyl cyclase 
activator, conferred a similar effect. Iloprost and treprostinil increased 
intracellular adenosine 3',5'-cyclic monophosphate (cAMP) levels, and iloprost 
also increased intracellular Ca(2+). Iloprost suppressed poly I:C-induced 
mitogen-activated protein kinase (MAPK) phospho-p38 and phospho-activating 
transcription factor (ATF)2 expression. Iloprost downregulated poly I:C-induced 
histone H3K4 trimethylation in the TNFA gene promoter region via suppressing 
translocation of histone 3 lysine 4 (H3K4)-specific methyltransferases MLL 
(mixed lineage leukemia) and WDR5 (WD repeat domain 5). Iloprost-treated mDCs 
inhibited IL-13, IFN-γ and IL-10 production by T cells. In conclusion, PGI(2) 
analogs enhance IL-10 and suppress TNF-α expression through the IP/EP2/EP4 
receptors-cAMP and EP1 receptor-Ca(2+) pathway. Iloprost suppressed TNF-α 
expression via the MAPK-p38-ATF2 pathway and epigenetic regulation by 
downregulation of histone H3K4 trimethylation.