Prostaglandin E(2) is a selective inducer of interleukin-12 p40 (IL-12p40) production and an inhibitor of bioactive IL-12p70 heterodimer.
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 E(2) (PGE(2)), 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 (TNFalpha)-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 TNFalpha/PGE(2) to induce IL-12p70 was not compensated by interferon gamma (IFNgamma), which strongly enhanced the lipopolysaccharide (LPS)-induced IL-12p70 production. In addition to the selective induction of IL-12p40 in TNFalpha-stimulated DCs, PGE(2) 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 PGE(2), 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 PGE(2)-matured DCs. (Blood. 2001;97:3466-3469)
Kaliński
P
P
Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, 1100 DE Amsterdam, The Netherlands. kalinskip@msx.upmc.edu
Vieira
P L
PL
Schuitemaker
J H
JH
de Jong
E C
EC
Kapsenberg
M L
ML
D023201:CD40 Ligand / Q000494:pharmacology; D003713:Dendritic Cells / Q000502:physiology; D019281:Dimerization; D015232:Dinoprostone / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D018664:Interleukin-12 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand; D018664:Interleukin-12; D007371:Interferon-gamma; D015232:Dinoprostone