The long-term objective of this research is to delineate the mechanisms hereby macrophage-secreted prostanoids (i.e. prostaglandins and thromboxanes) inhibit the activation of normal B cells and B lymphomas. First, selected prostanoids will be examined for their ability to promote B cell unresponsiveness, in conjunction with antigen-specific signals. This will be accomplished using an in vitro assay and purified hapten-specific B cells. Second, the role of B cell receptors for antigen and for the Fc portion of immunoglobulin in prostaglandin(PG)-enhanced negative signalling will be determined. This is important because in the presence of PG, cells may be negatively signalled or growth- inhibited via sIgM or Fc receptors. Third, since PGE2 inhibits macrophage activation, it may similarly block B cell activation. The effects of PGE2 on the activation of normal B cells and B lymphomas, stimulated by IL-4 or anti-IgM reagents, will be assessed. Activation will be monitored by increases in size, induction of membrane IL-I and class II expression. Inhibition of these events by PG may block proliferation, differentiation and ability to present antigen. Fourth, the presence of high or low affinity receptors for PGE2 will be examined using B lymphomas. Some lymphoma clones are growth-inhibited by PGE2, whereas others are resistant. The presence of PGE2 receptors on B lymphomas may confer susceptibility to this prostanoid. A binding assay will be used to detect this receptor and to determine whether its expression is altered by cell activation. Since relatively little is known about how arachidonic acid metabolites like PGE2 affect normal and neoplastic B cells, this research proposal would help fill that gap. Furthermore, understanding how prostanoids regulate B lymphomas may provide an avenue for new strategies to inhibit their growth in vivo.