Interleukin-4 and -13 Inhibit Tumor Necrosis Factor-α mRNA Translational Activation in Lipopolysaccharide-induced Mouse Macrophages

The production of tumor necrosis factor-α (TNF-α) by lipopolysaccharide (LPS)-stimulated macrophages can be markedly inhibited by the two closely related cytokines, interleukin (IL)-4 and IL-13. To investigate the molecular mechanism of this inhibition, we analyzed the effect of the two cytokines on TNF-α production and TNF-α mRNA accumulation in the mouse macrophage cell lines RAW 264.7 and J774 stimulated by LPS. Whereas LPS-induced TNF-α production is strongly suppressed by both cytokines, TNF-α mRNA accumulation is not significantly affected, indicating that IL-4 and IL-13 induce a translational repression of TNF-α mRNA. Transfection of reporter gene constructs containing different regions of the TNF-α gene revealed that the inhibitory action of IL-4 and IL-13 is mediated by the UA-rich sequence present in the TNF-α mRNA 3′-untranslated region.