In the present study, we demonstrate that TGF-beta is capable of enhancing macrophage ability to produce IL-10 in normal and EL4 tumor-bearing mice. We found the increase in IL-10 in ascitic fluid and IL-10 mRNA expression in macrophages in parallel with the TGF-beta level and tumor progression. The macrophage production of IL-10 in the tumor-bearing mice was significantly enhanced without LPS stimulation in vitro, compared with normal controls. To clarify the mechanism wherein increased IL-10 production was induced, anti-TGF-beta or anti-IL-10 Abs were administered to EL4-bearing mice. Administration of anti-TGF-beta Ab led to a reduction in the IL-10 contents in ascitic fluid of tumor-bearing mice; however, anti-IL-10 Ab administration did not prevent the increase in TGF-beta contents. Enhanced IL-10 production and mRNA expression of macrophages from the tumor-bearing mice were also reduced by anti-TGF-beta Ab administration. Both anti-TGF-beta and anti-IL-10 Ab administration restored the TNF-alpha production by macrophages in EL4-bearing mice. In normal macrophages, in vitro pretreatment with TGF-beta 1 potentiated IL-10 production, and when natural TGF-beta 1 was administered to normal mice, the recovered peritoneal macrophages showed enhanced IL-10 production. Based on the above findings it can be concluded that TGF-beta enhances macrophage ability to produce IL-10, which sheds a new light on the role of TGF-beta in the immune system.