INCREASED PGE(2) PRODUCTION MEDIATES THE IN-VITRO INHIBITORY EFFECT OF THE HUMAN-IMMUNODEFICIENCY-VIRUS P24 IMMUNOSUPPRESSIVE HEPTAPEPTIDE CH7

Previous work from our laboratory demonstrated that a synthetic heptap eptide (Ch7), corresponding to a conserved sequence of human immunodef iciency virus (HIV) core protein p24 (amino acids 232-238), was able t o specifically abrogate antigen-induced responses in cultures of norma l human peripheral blood lymphocytes (PBL). Addition of recombinant hu man interferon-gamma (IFN-gamma) to Ch7-suppressed cultures restored t he capacity to mount an antigen-specific antibody response, suggesting that a cytokine imbalance may be at the basis of the Ch7 immunosuppre ssive activity. In the present paper we show that the Ch7-dependent in vitro immunosuppression was accompanied by a significant up-regulatio n of prostaglandin E-2 (PGE(2)) production and induction of interleuki n-10 (IL-10)-secreting cells. In the presence of the PGE2 inhibitor in domethacin, IL-10 up-regulation was prevented and the induction of a s pecific antibody response was partially restored. PGE2 is indeed an im portant regulator of immune responses with the ability to differential ly affect cytokine production. Thus, our results demonstrate that the Ch7 immunosuppressive epitope may primarily act by up-regulating PGE(2 ) production and, through this mediator, by causing a cytokine dysregu lation, finally responsible for immune response suppression.