In vitro monocyte-derived macrophages (MDMac) and synovial fluid macrophages from inflamed joints differ from monocytes in their responses to interleukin 4 (IL-4). While IL-4 can suppress LPS-induced interleukin β (IL-β) and tumour necrosis factor α (TNF-α) production by monocytes, IL-4 can suppress LPS-induced IL-1β, but not TNFα production by the more differentiated cells. Recently we reported a correlation between the ability of IL-4 to regulate TNFα production by monocytes and the expression of the IL-4 receptor gamma chain or gamma common (γc chain). Like MDMac, interferon α (IFNα)-treated monocytes expressed less IL-4 receptor γc chain, reduced levels of IL-4-activated STAT6 and IL-4 could not suppress LPS-induced TNFα production. In addition, like monocytes and MDMac, IFNα-treated monocytes expressed normal levels of the IL-4 receptor α chain and IL-4 significantly suppressed LPS-induced IL-1β production. With addition of IFNα-neutralizing antibodies, the ability of IL-4 to suppress LPS-induced TNFα production with prolonged monocyte culture was restored. Detection of IFNα in synovial fluids from inflamed joints further implicates IFNα in the inability of IL-4 to suppress TNFα production by synovial fluid macrophages. This study identifies a mechanism for the differential expression of γc and varied responses to IL-4 by human monocytes compared with MDMac.