IL-12 and IL-4, respectively, dominate Th1 versus Th2 polarization. Additionally IL-4 can inhibit IL-12 p40 production in DC. Here we show that macrophages respond to bacterial CpG-DNA with IL-12 p40 production in an IL-4-sensitive manner. Analysis of the molecular mechanism of this inhibition shows that IL-4 acts by reducing the stability of IL-12 p40 mRNA as well as by affecting promoter activity. IL-4 did not affect early CpG-DNA-induced signal transduction. However, IL-4 reduced the activity of the IL-12 p40 promoter and when de novo transcription of IL-12 p40 mRNA was blocked, IL-4 led to acceleration of IL-12 p40 mRNA degradation. These data show that IL-4 regulates IL-12 p40 expression by influencing promoter activity and by interfering with mRNA stability.