TY - JOUR
T1 - IL-4 inhibits IL-2-induced tumoricidal activity and secretory functions of human monocytes
T2 - Modulation of IL-2 binding and IL-2 receptor βγ chain expression
AU - Bosco, M. C.
AU - Pulkki, K.
AU - Rowe, T. K.
AU - Zea, A. H.
AU - Musso, T.
AU - Longo, D. L.
AU - Varesio, L.
AU - Espinoza-Delgado, I.
PY - 1995
Y1 - 1995
N2 - Human monocytes express functional IL-2 receptors (IL-2R) and are directly activated by IL-2 to exert effector and secretory functions. In this study, we show that IL-4 selectively suppressed, in a dose-dependent manner, IL-2- induced monocyte tumoricidal activity, without affecting IFN-γ-dependent cytotoxicity. This effect was specific because a neutralizing anti-IL-4 mAb completely restored IL-2-activated cytolysis. Furthermore, IL-4 effectively blocked the secretion of proinflammatory cytokines by IL-2-stimulated monocytes. Binding studies with biotin-conjugated IL-2 demonstrated that monocyte stimulation with IL-2 increased IL-2 binding to the cell surface, and that treatment with IL-4 inhibited this augmentation, providing a possible explanation for the 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 expression of IL-2Rγ chain above the levels induced by IL-2 alone, whereas it did not significantly affect the expression of IL-2Rβ chain. Thus, the inhibition of IL-2 binding by IL-4 may be due to the recruitment of the γ chain into the IL-4-IL-4R system, making it unavailable for participation in the formation of IL-2 binding sites. These findings 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 play an important role in vivo as an inhibitory signal that controls the response of monocytes to IL-2.
AB - Human monocytes express functional IL-2 receptors (IL-2R) and are directly activated by IL-2 to exert effector and secretory functions. In this study, we show that IL-4 selectively suppressed, in a dose-dependent manner, IL-2- induced monocyte tumoricidal activity, without affecting IFN-γ-dependent cytotoxicity. This effect was specific because a neutralizing anti-IL-4 mAb completely restored IL-2-activated cytolysis. Furthermore, IL-4 effectively blocked the secretion of proinflammatory cytokines by IL-2-stimulated monocytes. Binding studies with biotin-conjugated IL-2 demonstrated that monocyte stimulation with IL-2 increased IL-2 binding to the cell surface, and that treatment with IL-4 inhibited this augmentation, providing a possible explanation for the 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 expression of IL-2Rγ chain above the levels induced by IL-2 alone, whereas it did not significantly affect the expression of IL-2Rβ chain. Thus, the inhibition of IL-2 binding by IL-4 may be due to the recruitment of the γ chain into the IL-4-IL-4R system, making it unavailable for participation in the formation of IL-2 binding sites. These findings 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 play an important role in vivo as an inhibitory signal that controls the response of monocytes to IL-2.
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M3 - Article
C2 - 7636206
AN - SCOPUS:0029162888
VL - 155
SP - 1411
EP - 1419
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 3
ER -