Inhibition of release of arachidonic acid, superoxide, and IL-1 from human monocytes by monoclonal anti-HLA class II antibodies: effects at proximal and distal points of inositol phospholipid hydrolysis pathway.
Incubation of human elutriator-purified monocytes with anti-HLA-DR or DQ antibody inhibited the release of arachidonic acid induced by serum-treated zymosan (STZ), a phagocytic stimulus that is known to induce inositol phospholipid hydrolysis and Ca2+ influx. However, only anti-HLA-DR antibody partially inhibited STZ-induced inositol phospholipid hydrolysis and concanavalin-A-induced Ca2+ influx. Incubation with anti-HLA-DR or -DQ antibody inhibited phorbol ester-induced AA release as well as superoxide production and IL-1 release. Inhibition of monocyte function by anti-class II antibodies was not accompanied by cAMP elevation. Furthermore, addition of exogenous db-cAMP and other agents (forskolin, cholera toxin, or 3-isobutyl-1-methyl-xanthine) that increase cAMP levels through different mechanisms, alone or in combination with anti-HLA antibodies, had no inhibitory effect on factor release. Our results demonstrate that perturbation of class II molecules down-modulates cell activation at more than one point of the signal transduction pathway with dominant inhibition distal to inositol phospholipid hydrolysis. They also suggest that the inhibition by anti-HLA class II antibody is probably not mediated via cAMP elevation.
Puri
J
J
Division of Hematology, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Bethesda, Maryland 20892.
Taplits
M
M
Alava
M
M
Bonvini
E
E
Hoffman
T
T
D000911:Antibodies, Monoclonal / Q000276:immunology*; D016718:Arachidonic Acid / Q000097:blood*; D002118:Calcium / Q000097:blood; D000242:Cyclic AMP / Q000097:blood / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000097:blood*; D015759:Ionomycin / Q000276:immunology; D009000:Monocytes / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000097:blood; D015398:Signal Transduction / Q000502:physiology; D013481:Superoxides / Q000097:blood*; D013755:Tetradecanoylphorbol Acetate / Q000378:metabolism; D015054:Zymosan / Q000037:antagonists & inhibitors
D000911:Antibodies, Monoclonal; D000949:Histocompatibility Antigens Class II; D007375:Interleukin-1; D010716:Phosphatidylinositols; D013481:Superoxides; D016718:Arachidonic Acid; D015759:Ionomycin; D015054:Zymosan; D000242:Cyclic AMP; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium