Interleukin 1β (IL-1β) suppresses the IL-6-dependent induction of type II acute-phase response genes, but the underlying mechanism for this suppression remains uncertain. Here we report that treatment of human hepatocullular carcinoma HepG2 cells with IL-1β inhibited the IL-6-dependent binding of signal transducer and activator of transcription factor (STAT)1, but not that of STAT3, to the high-affinity serum-inducible element (‘SIE’). Furthermore, IL-1β selectively down-regulated the IL-6-induced tyrosine phosphorylation of STAT1 without affecting the level of STAT1 or tyrosine phosphorylation of STAT3. Kinase assays in vitro indicated that the inhibition of STAT1 phosphorylation by IL-1β was not due to an upstream blockade of Janus kinase (JAK1 or JAK2) activation. However, pretreatment with the proteasome inhibitor MG132 under conditions that prevented the IL-1β-dependent activation of the nuclear factor NF-κB also blocked the inhibitory effect of IL-1β on IL-6-activated STAT1. In related experiments, the protein tyrosine phosphatase inhibitor Na3VO4 also antagonized the inhibitory effect of IL-1β on the activation of STAT1 by IL-6. Taken together, these findings indicate that, by using a proteasome-dependent mechanism, IL-1β concomitantly induces NF-κB activation and dephosphorylates IL-6-activated STAT1; the latter might partly account for the inhibition by IL-1β of the IL-6-dependent induction of type II acute-phase genes.

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