Interleukin-4 down-regulates both forms of tumor necrosis factor receptor and receptor-mediated apoptosis, NF-kappa B, AP-1, and c-Jun N-terminal kinase - Comparison with interleukin-13

The activity of tumor necrosis factor (TNF), a proinflammatory cytokine, is regulated by a number of other cytokines, including interleukin (IL)-4, Ho w IL-4 regulates various activities of TNF is not fully understood. In the present report, we investigated the effect of IL-4 on the cell surface TNF receptors in human histiocytic lymphoma U-937 cells. Pretreatment of cells with IL-4 downregulated TNF receptors in a dose- and time-dependent manner; an almost 90% decrease occurred with 10 ng/ml IL-4 treatment for 24 h, Sca tchard analysis revealed that the decrease was due to receptor number and n ot affinity, IL-13, which shares a common receptor subunit and various biol ogical activities with IL-4, had no effect on TNF receptors, IL-4's effect on TNF receptors was not cell type-specific, since decreases also occurred on various epithelial and T cells. Both the p60 and p80 forms of the TNF re ceptor were down-regulated to the same extent. Western blot showed that. IL -4 induced shedding of the TNF receptors, The decrease of TNF receptors by IL-4 was accompanied by down-regulation of TNF-induced activities, includin g cytotoxicity, caspase-3 activation, NF-kappa B and AP-1 activation, and c -Jun N-terminal kinase induction. Wortmannin reversed the IL-4-induced TNF receptor down-regulation and all other measured cellular responses, indicat ing a critical role of phosphatidylinositol 3-kinase. Rapamycin also blocke d the effect of IL-4-induced regulation, thus suggesting the role of p70 S6 kinase, Overall, our results suggest that TNF receptor down-regulation by IL-4 plays a critical role in the antagonistic effects of IL-4 on TNF-induc ed cellular responses and that this mechanism differs from that of IL-13.