Abstract
During human immunodeficiency virus infection and allergic diseases, characterized by a dominant T helper (Th) 2 response, overproduction of prostaglandin E2 (PGE2) is observed. In this paper we studied the effect of PGE2 on interleukin (IL)-12 synthesis, because this cytokine has been described to be essential in induction of Th1 responses. IL-12 synthesis was induced in monocytes that were stimulated with Neisseria meningitidis-derived lipopolysaccharide in whole blood cultures. PGE2 almost completely inhibited lipopolysaccharide induced IL-12 production, whereas IL-6 production was only partially inhibited by PGE2. In contrast, the production of IL-10 was approximately twofold enhanced at these conditions. The effects of PGE2 were due to its cAMP-inducing capacity, since they could be mimicked by other cAMP inducers. Recombinant human IL-10 also inhibited IL-12 and IL-6 production. However, the inhibitory effect of PGE2 on IL-12 production was independent of IL-10 since neutralizing anti-IL-10 antibodies were unable to reverse this inhibition. These results suggest that the capacity of an antigen to induce PGE2 synthesis may play a crucial role in the development of either a Th1 or Th2 response.
Highlights
In this report we describe another mechanism of action of prostaglandin E2 (PGE2) on induction of Th2 responses, which represents an inhibition by PGE2 of the production of IL-12 by the APC
In vitro IL-12 production by peripheral blood monocytes is induced by bacterial products such as LPS and Staphylococcus aureus Cowan I strain (SAC) [12]
We used LPS from N. meningitidis to study the regulation of IL-12 production
Summary
AntibodiesandReagents. Anti-IL-12mAb Cll.79 and C8.6 [12] wereprovidedby Dr G. Trinchieri(TheWistar Institute,Philadelphia, PA).The antibodiesrecognizeboth IL-12p40 and the bioacriveheterodimerp70, consistingofp40 and p35, as described[12]. IL-12p40 and p70 areproducedin parallelbyhumanPBMC,which is the result of p40 mRNA upregulation, whereas p35 mRNA expressionis only minimallyregulated[12, 13]. Anti-ILl0 mAb B-T10andB-N10wereproducedat Innotherapie(Besan~on,France). PGE2, 3-isobutyl-l-methylxanthine(IBMX)and N-2-O-dibutyrylcAMP (DBcAMP)wereobtainedfrom SigmaChemicalCo. (St. Louis, MO). Recombinanthuman (rh) IL-10was a kind giftfrom Dr R. de WaalMalefijt(DNAX, PaloAlto, CA). Neisseriameningitidis-derived LPS was a gift from Dr J. Poolman (RIVM, Bilthoven, The Netherlands).
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