Inflammation, Vol. 16, No. 1, 1992 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 Phosi?holipid Hydrolysis Pathway JOSEPH PURl, t MICHAEL TAPLITS, MARIA ALAVA, EZIO BONVINI, and THOMAS HOFFMAN Laboratory of Cell Biology, Division of Hematology Center for Biologics Evaluation and Research iZ S. Food and Drug Administration Bethesda, Maryland 20892 Abstract--Incubation of human elutriator-purified monocytes with anti-HLA-DR or DQ antibody inhibited the release of arachidonic acid induced by serum-treated zy- mosan (STZ), a phagoc:/tic stimulus that is known to induce inositol phospholipid hydrolysis and Ca 2§ influx. However, only anti-HLA-DR antibody partially inhib- ited 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 ele- vation. Furthermore, addition of exogenous db-cAMP and other agents (forskolin, cholera toxin, or 3-isobutyl-l-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 hydrol- ysis. They also suggest tlaat the inhibition by anti-HLA class II antibody is probably not mediated via cAMP ~levation. INTRODUCTION Human leukocyte antigen (HLA) class II molecules, encoded within the major histocompatibility complex (MHC) play a key role in the immune response by ~ Visiting Scientist, The Weizm~ nn Institute of Science, Rehovot, Israel. 31 0360-3997/92/02004)031 $06.50/0 9 1992 Plenum Publishing Corporation