Entamoeba histolytica suppresses gamma interferon-induced macrophage class II major histocompatibility complex Ia molecule and I-A beta mRNA expression by a prostaglandin E2-dependent mechanism.
The surface expression of class II major histocompatibility complex immune-associated (Ia) antigen is a principal accessory function of macrophages for antigen-specific T-cell activation and immunoregulation. To explore the mechanisms of impaired cell-mediated immunity in invasive amebiasis, we investigated the effects of Entamoeba histolytica proteins on gamma interferon (IFN-gamma)-induced Ia expression by murine bone marrow-derived macrophages. Pretreatment of macrophages with secreted (conditioned medium) or whole soluble amebic proteins inhibited the induction of IFN-gamma-induced surface Ia antigen expression by 30 to 61% but had no effect on surface Ia molecules already expressed. By Northern (RNA) blot analysis, amebic proteins suppressed IFN-gamma-induced macrophage I-A beta mRNA accumulation by 36% but did not alter the constitutive levels of actin mRNA expression. E. histolytica stimulated macrophages to produce high levels of prostaglandin E2 (PGE2) as determined by reverse-phase high-pressure liquid chromatography and quantification by PGE2-specific radioimmunoassay. Inhibition of PGE2 biosynthesis with the cyclooxygenase inhibitor indomethacin abrogated ameba-induced suppression of Ia antigen by 60%, whereas exogenously added PGE2 decreased IFN-gamma-induced macrophage Ia expression by 44%. Our results suggest that the mechanism whereby E. histolytica suppresses IFN-gamma-induced macrophage surface Ia molecule synthesis and I-A beta mRNA expression is by stimulating the production of PGE2, which acts in an autocrine fashion for immunoregulation. E. histolytica subverting critical macrophage accessory function via PGE2 biosynthesis is a novel strategy which the parasite uses to suppress host defenses.
Wang
W
W
Institute of Parasitology of McGill University, Ste-Anne de Bellevue, Quebec, Canada.
Chadee
K
K
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D015232:Dinoprostone / Q000378:metabolism*; D004748:Entamoeba histolytica / Q000276:immunology*; D005786:Gene Expression Regulation; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D015800:Protozoan Proteins / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis
D000949:Histocompatibility Antigens Class II; D015800:Protozoan Proteins; D012333:RNA, Messenger; D007371:Interferon-gamma; D015232:Dinoprostone