The monocyte-derived cytokines, tumor necrosis factor alpha (TNF) and interleukin-1 beta (IL-1), are central regulators of the immune response, but the physiologic stimuli for their release remain largely undefined. We have found that engagement of three monocyte glycoproteins: LFA-3, CD44 and CD45 by specific monoclonal antibodies immobilized on plastic induced TNF and IL-1 release. It was shown that this response was not due to contaminating endotoxin and that five monoclonal antibodies specific for other monocyte surface antigens failed to induce TNF or IL-1 release. In addition, TNF was released when monocyte LFA-3 bound immobilized purified CD2, which is its physiologic receptor. Thus, a receptor-ligand interaction that mediates cell-cell adhesion, can transmit the necessary signals for the release of monokines.