IL-4 INHIBITS IL-2-INDUCED TUMORICIDAL ACTIVITY AND SECRETORY FUNCTIONS OF HUMAN MONOCYTES - MODULATION OF IL-2 BINDING AND IL-2 RECEPTOR BETA-GAMMA CHAIN EXPRESSION

Human monocytes express functional IL-2 receptors (IL-2R) and are dire ctly activated by IL-2 to exert effector and secretory functions. In t his study, we show that IL-4 selectively suppressed, in a dose-depende nt manner, IL-2-induced monocyte tumoricidal activity, without affecti ng IFN-gamma-dependent cytotoxicity. This effect was specific because a neutralizing anti-IL-4 mAb completely restored IL-2-activated cytoly sis. Furthermore, IL-4 effectively blocked the secretion of proinflamm atory cytokines by IL-2-stimulated monocytes. Binding studies with bio tin-conjugated IL-2 demonstrated that monocyte stimulation with IL-2 i ncreased IL-2 binding to the cell surface, and that treatment with IL- 4 inhibited this augmentation, providing a possible explanation for th e decreased responsiveness of monocytes to IL-2 in the presence of IL- 4. However, IL-4 suppressive effects could not be ascribed to the down -regulation of the individual components of the IL-2R complex. In fact , co-treatment of monocytes with IL-2 and IL-4 increased the expressio n of IL-2R gamma chain above the levels induced by IL-2 alone, whereas it did not significantly affect the expression of IL-2R beta chain. T hus, the inhibition of IL-2 binding by IL-4 may be due to the recruitm ent of the gamma chain into the IL-4-IL-4R system, making it unavailab le for participation in the formation of IL-2 binding sites. These fin dings provide the first evidence of the ability of IL-4 to suppress IL -2-mediated activation of human monocytes and suggest that IL-4 may pl ay an important role in vivo as an inhibitory signal that controls the response of monocytes to IL-2.