Prostaglandin E2 is a selective inducer of interleukin-12 p40 (IL-12p40) production and an inhibitor of bioactive IL-12p70 heterodimer

Abstract

Interleukin-12 p70 (IL-12p70) heterodimer, composed of p35 and p40 subunits, is a major Th1-driving cytokine, promoting cell-mediated immunity. In contrast, IL-12p40 homodimer, secreted by APC in the absence of p35 expression, and free p40 monomer do not mediate IL-12 activity but act as IL-12 antagonists. Here it is reported that prostaglandin E2 (PGE2), an inflammatory mediator with a previously known Th2-driving function, dose-dependently enhances the IL-12p40 mRNA expression and the secretion of IL-12p40 protein in human tumor necrosis factor-alpha (TNFα)–stimulated immature dendritic cells (DCs). This effect is selective and is not accompanied by the induction of IL-12p35 expression or by secretion of IL-12p70 heterodimer. Inability of TNFα/PGE2 to induce IL-12p70 was not compensated by interferon gamma (IFNγ), which strongly enhanced the lipopolysaccharide (LPS)–induced IL-12p70 production. In addition to the selective induction of IL-12p40 in TNFα-stimulated DCs, PGE2 inhibited the production of IL-12p70 and IL-12p40 in DCs stimulated with LPS or CD40 ligand. These data suggest an additional level of the Th2-promoting activity of PGE2, via selective induction of IL-12p40. Selective induction of IL-12p40 and suppression of bioactive IL-12p70 may have negative impact on anticancer vaccination with PGE2-matured DCs.