Prostaglandin I(2) analogues enhance growth-related oncogene-alpha expression in human monocyte-derived dendritic cells

Abstract

Chemokines for neutrophils such as growth-related oncogene-alpha (GRO-alpha) are important in patients with refractory or severe asthma. Prostaglandin I(2) (PGI(2)) analogues were regarded as potential treatments for asthma. Dendritic cells (DCs) are the professional antigen-presenting cells and play a critical role in regulating immune response. However, it is unknown whether PGI(2) analogues have regulatory effects on GRO-alpha expression in human monocyte-derived DCs (MDDCs). The human MDDCs were pretreated with iloprost and treprostinil (two PGI(2) analogues) or forskolin, a cyclic adenosine monophosphate (cAMP) activator, before stimulation with lipopolysaccharide (LPS). In some cases, I prostanoid (IP) receptor and E prostanoid (EP) antagonists were pretreated before PGI(2) analogue treatment. To investigate the intracellular signaling, nuclear factor (NF)-kappaB inhibitor and the mitogen-activated protein kinase (MAPK) inhibitors were pretreated before PGI(2) analogue treatment. GRO-alpha was measured by enzyme-linked immunosorbent assay. Intracellular signaling was also investigated by Western blot. Iloprost and treprostinil enhanced LPS-induced GRO-alpha expression in MDDCs. This effect could be reversed by an I prostanoid receptor antagonist, CAY10449, but not EP receptor antagonists. Forskolin conferred a similar modulating effect as that noted in iloprost- and treprostinil-treated MDDCs. PGI(2) analogue-enhanced LPS-induced GRO-alpha expression was reduced by MAPK-p38 inhibitor, SB203580. PGI(2) analogues enhanced LPS-induced phospho-p38 expression. PGI(2) analogues enhanced LPS-induced GRO-alpha expression via the IP receptor-cAMP and p38-MAPK pathways in human MDDCs, which may further recruit neutrophil accumulation and adversely affect patients with refractory or severe asthma because of airway neutrophilia. These effects should be considered for PGI(2) analogues as candidates for the treatment of asthma.