Differential regulation of tumour necrosis factor-alpha mRNA degradation in macrophages by interleukin-4 and interferon-gamma.

Interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) have been reported previously to mediate similar as well as antagonistic effects on murine macrophage functions. One effect common to both is the enhancement of tumour necrosis factor-alpha (TNF-alpha) secretion in macrophages. To assess further the effects of these two lymphokines on macrophage TNF-alpha production, we investigated the role of these lymphokines in the induction and stability of TNF-alpha messages along with interleukin-1 (IL-1) as a comparison. IFN-gamma and IL-4 increased lipopolysaccharide (LPS)-induced TNF-alpha, IL-1 steady-state message levels. In contrast to IL-1 messages, whose degradation was not significantly affected by either lymphokine, the stability of TNF-alpha messages differed after IFN-gamma and IL-4 treatment. Although IL-4 treatment increased the TNF-alpha transcription rate, an increase in the degradation rate of TNF-alpha mRNA in the IL-4-treated cells resulted in a lower level of steady-state mRNA than in the IFN-gamma-treated cells. Additionally, a 18,000 MW cytoplasmic factor was found to have specific binding activity to the AU-rich sequences of the TNF-alpha message in peritoneal macrophages. Although the binding activity of this factor was not affected by either IFN-gamma or IL-4, the binding of the factor to AU-rich sequences appeared to be important in the rapid degradation of TNF-alpha messages. Thus IFN-gamma and IL-4 may differentially affect the post-transcriptional control of TNF-alpha gene expression. And this lymphokine-mediated post-transcriptional control of the TNF-alpha gene does not appear to involve the alteration of binding activity of the 18,000 MW AU-rich sequence binding factor.