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 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-gamma-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-2R gamma chain above the levels induced by IL-2 alone, whereas it did not significantly affect the expression of IL-2R beta chain. Thus, the inhibition of IL-2 binding by IL-4 may be due to the recruitment of the gamma 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.
Bosco
M C
MC
Laboratory of Experimental Immunology, Inc/DynCorp, NCI-FCRDC, Frederick, MD 21702, USA.
Pulkki
K
K
Rowe
T K
TK
Zea
A H
AH
Musso
T
T
Longo
D L
DL
Varesio
L
L
Espinoza-Delgado
I
I
D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D002277:Carcinoma / Q000473:pathology; D003110:Colonic Neoplasms / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007376:Interleukin-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015847:Interleukin-4 / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects* / Q000502:physiology; D011485:Protein Binding / Q000187:drug effects; D015375:Receptors, Interleukin-2 / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D016207:Cytokines; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D015847:Interleukin-4