Cross-talk between interleukin 1 beta (IL-1 beta) and IL-6 signalling pathways: IL-1 beta selectively inhibits IL-6-activated signal transducer and activator of transcription factor 1 (STAT1) by a proteasome-dependent mechanism

Interleukin 1 beta (IL-1 beta) suppresses the IL-6-dependent induction of t ype II acute-phase response genes, but the underlying mechanism for this su ppression remains uncertain, Here we report that treatment of human hepatoc ullular carcinoma HepG2 cells with IL-1 beta inhibited the IL-6-dependent b inding 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-1/beta, selectively down-regulated the IL-6-induced tyros ine phosphorylation of STAT1 without affecting the level of STAT1 or tyrosi ne phosphorylation of STAT3. Kinase assays in vitro indicated that the inhi bition of STAT1 phosphorylation by IL-1 beta was not due to an upstream blo ckade of Janus kinase (JAK1or JAK2) activation, However, pretreatment with the proteasome inhibitor MG132 under conditions that prevented the IL-1 bet a -dependent activation of the nuclear factor NF-kappaB also blocked the in hibitory effect of IL-1 beta on IL-6-activated STAT1, In related experiment s, the protein tyrosine phosphatase inhibitor Na3VO4 also antagonized the i nhibitory effect of IL-1 beta on the activation of STAT1 by IL-6, Taken tog ether, these findings indicate that, by using a proteasome-dependent mechan ism, IL-1 beta concomitantly induces NF-kappaB activation and dephosphoryla tes IL-6-activated STAT1; the latter might partly account for the inhibitio n by IL-1 beta of the IL-6-dependent induction of type II acute-phase genes .