ENTAMOEBA-HISTOLYTICA SUPPRESSES GAMMA-INTERFERON-INDUCED MACROPHAGE CLASS-II MAJOR HISTOCOMPATIBILITY COMPLEX IA MOLECULE AND I-A-BETA MESSENGER-RNA EXPRESSION BY A PROSTAGLANDIN E(2)-DEPENDENT MECHANISM

The surface expression of class II major histocompatibility complex im mune-associated (Ia) antigen is a principal accessory function of macr ophages for antigen-specific T-cell activation and immunoregulation. T o explore the mechanisms of impaired cell-mediated immunity in invasiv e amebiasis, we investigated the effects of Entamoeba histolytica prot eins on gamma interferon (IFN-gamma)-induced Ia expression by murine b one marrow-derived macrophages. Pretreatment of macrophages with secre ted (conditioned medium) or whole soluble amebic proteins inhibited th e induction of IFN-gamma-induced surface Ia antigen expression by 30 t o 61% but had no effect on surface Ia molecules already expressed. By Northern (RNA) blot analysis, amebic proteins suppressed IFN-gamma-ind uced macrophage I-A beta mRNA accumulation by 36% but did not alter th e constitutive levels of actin mRNA expression. E. histolytica stimula ted macrophages to produce high levels of prostaglandin E(2) (PGE(2)) as determined by reverse-phase high-pressure liquid chromatography and quantification by PGE(2) specific radioimmunoassay. Inhibition of PGE , biosynthesis with the cyclooxygenase inhibitor indomethacin abrogate d ameba-induced suppression of Ia antigen by 60%, whereas exogenously added PGE, decreased IFN-gamma-induced macrophage Ia expression by 44% . Our results suggest that the mechanism whereby E. histolytica suppre sses IFN-gamma-induced macrophage surface Ia molecule synthesis and I- AB mRNA expression is by stimulating the production of PGE(2), which a cts in an autocrine fashion for immunoregulation. E. histolytica subve rting critical macrophage accessory function via PGE(2) biosynthesis i s a novel strategy which the parasite uses to suppress host defenses.