Prostaglandin E₂ augments IL-10 signaling and function

In inflamed joints of rheumatoid arthritis, PGE₂ is highly expressed, and IL-10 and IL-6 are also abundant. PGE₂ is a well-known activator of the cAMP signaling pathway, and there is functional cross-talk between cAMP signaling and the Jak-STAT signaling pathway. In this study, we evaluated the modulating effect of PGE₂ on STAT signaling and its biological function induced by IL-10 and IL-6, and elucidated its mechanism in THP-1 cells. STAT phosphorylation was determined by Western blot, and gene expression was analyzed using real-time PCR. Pretreatment with PGE₂ significantly augmented IL-10-induced STAT3 and STAT1 phosphorylation, as well as suppressors of cytokine signaling 3 (SOCS3) and IL-1R antagonist gene expression. In contrast, PGE₂ suppressed IL-6-induced phosphorylation of STAT3 and STAT1. These PGE₂-induced modulating effects were largely reversed by actinomycin D. Pretreatment with dibutyryl cAMP augmented IL-10-induced, but did not change DL-6-induced STAT3 phosphorylation. Misoprostol, an EP2/3/4 agonist, and butaprost, an EP2 agonist, augmented IL-10-induced STAT3 phosphorylation and SOCS3 gene expression, but sulprostone, an EP1/3 agonist, had no effect H89, a protein kinase A inhibitor, and LY294002, a PI3K inhibitor, diminished PGE₂-mediated augmentation of IL-10-induced STAT3 phosphorylation. In this study, we found that PGE ₂ selectively regulates cytokine signaling via increased intracellular cAMP levels and de novo gene expression, and these modulating effects may be mediated through EP2 or EP4 receptors. PGE₂ may modulate immune responses by alteration of cytokine signaling in THP-1 cells.