Abstract
Chemokines play important roles in asthma. Prostaglandin I2 (PGI2) analogue is recently suggested as a candidate for treating asthma. However, the effects of PGI2 analogues on the expression of Th1- and Th2-related chemokines are unknown. To this end, we investigated the in vitro effects of PGI2 analogues on the expression of Th1-related chemokine interferon-γ-inducible protein-10 (IP-10/CXCL10) and Th2-related chemokine macrophage-derived chemokine (MDC/CCL22) in human monocytes. The human monocytes were pretreated with iloprost and treprostinil before lipopolysaccharide (LPS) stimulation. IP-10 and MDC were measured by ELISA. Intracellular signaling was investigated by cyclic adenosine monophosphate (cAMP) assay, western blot and chromatin immunoprecipitation. PGI2 analogues enhanced MDC, but suppressed IP-10 expression in LPS-stimulated monocytes. These effects were reversed by the I prostanoid (IP) receptor antagonist (CAY10449), peroxisomal proliferators-activated receptor (PPAR)-α antagonist (GW6741) and PPAR-γ antagonist (GW9662). PGI2 analogues increased intracellular cAMP levels. Forskolin, an adenyl cyclase activator, conferred similar effects. PGI2 analogue-enhanced MDC expression was reduced by nuclear factor (NF) κB inhibitor (BAY 117085) and mitogen-activated protein kinase (MAPK)-p38 inhibitor (SB203580). PGI2 analogues up-regulated phospho-p65 and phospho-p38 but down-regulated phospho-ERK expression. Iloprost enhanced H3 acetylation in MDC promoter area and suppressed H3 acetylation, H3K4, and H3K36 trimethylation in IP-10 promoter area. PGI2 analogues enhanced MDC expression via the I prostanoid-receptor-cAMP, PPAR-α and PPAR-γ, NFκB-p65, MAPK-p38-ATF2 pathways and increasing histone acetylation, and suppressed IP-10 expression via the IP-receptor-cAMP, PPAR-γ, MAPK-ERK-ELK1 pathways and inhibiting histone acetylation and trimethylation in LPS-stimulated monocytes. PGI2 analogues may therefore increase Th2 recruitment and inflammation.
Original language | English |
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Pages (from-to) | 29-41 |
Number of pages | 13 |
Journal | Journal of Molecular Medicine |
Volume | 89 |
Issue number | 1 |
DOIs | |
Publication status | Published - Jan 2011 |
Keywords
- Epigenetics
- Interferon-γ-inducible protein-10
- Macrophage-derived chemokine
- Monocytes
- Prostaglandin I
ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery
- Genetics(clinical)