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

Abstract

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 is induced in the pathological processes. IL-23 is a heterodimer composed of p19 and p40, the latter being shared with IL-12. We previously reported that prostaglandin (PG) E 2 promotes CD40-mediated induction of Il23a (p19) expression through its E receptor subtype 4 (EP4) receptor in splenic dendritic cells (DCs). Here, we have analyzed signaling pathways regulating Il23a induction in the cross talk between EP4 and CD40 in bone marrow-derived DCs. We found that PGE 2 synergistically induced Il23a transcription with CD40 signaling. An EP4 agonist, but not agonists of EP1, EP2, or EP3, reproduced this action. Stimulation of CD40 with an agonist antibody evoked biphasic induction of Il23a expression, with the early phase peaking at 1 h and the late phase peaking at 12 h and lasting up to 36 h after stimulation, whereas induction by lipopolysaccharide or tumor necrosis factor-a was transient. The early phase induction by CD40 stimulation was absent in DCs derived from Nfkb1-deficient mice, and the late phase induction was eliminated by RNA interference of nuclear factor-kappa B (NF-kB) p100 subunit. Further, cAMP response element-binding protein (CREB) depletion completely eliminated the induction of Il23a by CD40 stimulation. The addition of the EP4 agonist amplified the induction in both phases through the cAMP-protein kinase A (PKA) pathway. These results suggest that Il23a expression in DCs is synergistically triggered by the PG E 2 -EP4-cAMP-PKA pathway and canonical/non-canonical NF-kB pathways and CREB activated by CD40 stimulation. Cellular & Molecular Immunology

T cell–intrinsic prostaglandin E2-EP2/EP4 signaling is critical in pathogenic TH17 cell–driven inflammation

“…Furthermore, we detected an increase in S536 phosphorylation of NF-κB p65 (pp65) in response to db-cAMP, IL-23, or both at 24 hours ( Fig 3 , E ) and an increase in S933 phosphorylation of NF-κB p105 subunit, a precursor of p50, in response to db-cAMP alone and its combination with IL-23 in T H 17 cells ( Fig 3 , E ). The latter is consistent with our previous finding in dendritic cells that PGE 2 -cAMP signaling activates the p50 subunit 54 and a report that phosphorylation of p105 S933 is PKA dependent. 55 Therefore we examined the involvement of NF-κB in Il23r induction by using Nfkb1 -deficient mice (p105 knockout [KO]) or CTP-NBD, an NF-κB inhibitor.…”

Frontline Science: c-Myc regulates P-selectin glycoprotein ligand-1 expression in monocytes during HIV-1 infection

“…Additionally, the model recapitulates robust activation of the MAPK ERK and weaker, transient activation of JNK, as described previously (Fig. 5B) [57,58].…”

Prostaglandin receptor EP4 expression by Th17 cells is associated with high disease activity in ankylosing spondylitis

“…This unique role of EP4 can be explained by different signaling pathways of EP2 and EP4. While the receptors share the cAMP pathway, EP4 signaling additionally activates PI3K/AKT, a pathway that controls Th17 cell differentiation [44][45][46][47][48] (Fig. 5).…”