Prostaglandin E2-EP4 signaling persistently amplifies CD40-mediated induction of IL-23 p19 expression through canonical and non-canonical NF-κB pathways.

摘要: While there is mounting evidence that interleukin (IL)-23-IL-17 axis plays a critical role in the pathogenesis of various autoimmune diseases, much remains to be elucidated on how IL-23 induced pathological processes. heterodimer composed p19 and p40, latter being shared with IL-12. We previously reported prostaglandin (PG) E2 promotes CD40-mediated induction Il23a (p19) expression through its E receptor subtype 4 (EP4) splenic dendritic cells (DCs). Here, we have analyzed signaling pathways regulating cross talk between EP4 CD40 bone marrow-derived DCs. found PGE2 synergistically transcription signaling. An agonist, but not agonists EP1, EP2, or EP3, reproduced this action. Stimulation an agonist antibody evoked biphasic expression, early phase peaking at 1 h late 12 lasting up 36 after stimulation, whereas by lipopolysaccharide tumor necrosis factor-α was transient. The stimulation absent DCs derived from Nfkb1-deficient mice, eliminated RNA interference nuclear factor-kappa B (NF-κB) p100 subunit. Further, cAMP response element-binding protein (CREB) depletion completely stimulation. addition amplified both phases cAMP-protein kinase A (PKA) pathway. These results suggest triggered PG E2-EP4-cAMP-PKA pathway canonical/non-canonical NF-κB CREB activated