IL‐12/IL‐23 production induced by Toll‐like receptor agonist primed myeloid dendritic cells is differentially regulated by prostaglandin E2

Abstract

DCs are potent APCs. Besides providing signal one and two in T cell activation, DCs critically provide third signals that direct T cell polarization. Important third signaling molecules produced by DCs include IL‐12 and IL‐23. IL‐12, however, is anti‐angiogenic and enhances anti‐tumor immunity while IL‐23 is pro‐angiogenic and is linked with chronic inflammation associated tumorigenesis. We examined the role of PGE2, a ubiquitous inflammatory molecule, in regulating IL‐12 and IL‐23 production by myeloid DCs. TLR agonists comparably matured DCs whether used singly, in pairs, or in conjunction with IFN‐γ. Maximal IL‐12 production, however, required TLR agonist pairing or combinations of single TLR agonist with IFN‐γ. Adding PGE2 enhanced the migratory capacity of all DCs. PGE2 also significantly inhibited IL‐12 production while increasing the production of IL‐23. PGE2‐treated, TLR agonist‐activated DCs also demonstrated an enhanced ability to activate Th17 cells at the expense of Th1 in the allogenic MLR. Moreover, addition of PGE2 inhibited TLR agonist‐activated DC from sensitizing high avidity, tumor‐recognizing CTL. Because of the profound functional divergence of the IL‐12/Th1 and the IL‐23/Th17 axis as it relates to cancer resistance, the balance of IL‐12 and IL‐23 production by DC may play a critical role in regulating tumor promotion or regression and should be considered in tumor vaccine design.