The anti-inflammatory effects of IL-4 on activated monocytes differ from those on monocyte-derived macrophages (MDMac). While IL-4 suppresses LPS-induced IL-1β, IL-12, IL-10 and TNFα production by monocytes, IL-4 suppresses only IL-1β and IL-12 production by MDMac. The U937 and Mono Mac 6 cell lines have similar cytokine responses to IL-4 as monocytes and MDMac, respectively. The IL-4Rα and IL-2Rγ (γc) chains are well-characterized components of the IL-4 receptor. Cross-linking studies with 125I-IL-4 revealed that for monocytes and U937 cells, the binding of IL-4 to the receptor components was approximately 1:1 for IL-4Rα:γc. In contrast, for MDMac and Mono Mac 6 cells that have a relative reduction in γc surface expression, the binding of IL-4 to IL-4Rα:γc was approximately 3:1. Furthermore, IL-4 induced IL-4Rα chain phosphorylation more rapidly in MDMac and Mono Mac 6 cells than in monocytes and U937 cells. This study identifies a correlation between altered 125I-IL-4 cross-linking to IL-4Rα:γc, IL-4-induced signaling and regulation of pro-inflammatory cytokine production by IL-4.