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

Abstract

The production of tumor necrosis factor-␣ (TNF-␣) 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-␣ production and TNF-␣ mRNA accumulation in the mouse macrophage cell lines RAW 264.7 and J774 stimulated by LPS. Whereas LPS-induced TNF-␣ production is strongly suppressed by both cytokines, TNF-␣ mRNA accumulation is not significantly affected, indicating that IL-4 and IL-13 induce a translational repression of TNF-␣ mRNA. Transfection of reporter gene constructs containing different regions of the TNF-␣ gene revealed that the inhibitory action of IL-4 and IL-13 is mediated by the UArich sequence present in the TNF-␣ mRNA 3-untranslated region. Tumor necrosis factor-␣ (TNF-␣)1 is a pleiotropic cytokine secreted by different cell types including macrophages, mastocytes, T and B lymphocytes, and natural killer cells in response to various stimuli (lipopolysaccharide (LPS), viruses, parasites, etc.) (1). A wide variety of cell types express TNF-␣ receptors, and the pleiotropism of TNF-␣ results from the complexity of the signal transduction pathways that are activated by its receptors. TNF-␣ is characterized by cytostatic and cytolytic effects on tumor cells of different origins (2), by antiviral properties (3), and by its important role in the activation of the immune system upon host invasion (4). TNF-␣ has also been identified as a major mediator of inflammatory processes, one of the most dramatic being Gram-negative endotoxic shock (1). Indeed, upon exposure to LPS or other agents simulating host invasion, macrophages produce large amounts of TNF-␣ that are released in the circulatory system. High levels of circulating TNF-␣ trigger a state of shock and tissue injury that carries an extremely high mortality rate (1).The expression of the TNF-␣ gene in mouse macrophages is regulated at the transcriptional (5, 6) and translational (1) levels. In resting macrophages, TNF-␣ synthesis is low because TNF-␣ gene transcription is weak and TNF-␣ mRNA translation is severely repressed. The translational repression is mediated by the UA-rich sequence present in the TNF-␣ mRNA 3Ј-untranslated region (1). Macrophage activation by LPS results in NF-B-dependent activation of TNF-␣ gene transcription, derepression of TNF-␣ mRNA translation, and secretion of TNF-␣ protein. TNF-␣ production by macrophages can be down-regulated by various agents including cytokines like IL-4 and IL-13 (7, 12). IL-4 and IL-13 are two closely related cytokines that are synthesized mainly by activated T lymphocytes (7,8). Both cytokines share many biological activities including the activation of B cell proliferation, IgE switching, and inhibition of inflammatory cytokine production (9 -11). TNF-␣ is one of the major inflammatory cytokines being repressed by IL-4 and IL-13. However, the molecular mechanism of this regulation has not been elucidate...

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