Lipopolysaccharide induces in macrophages the synthesis of the suppressor of cytokine signaling 3 and suppresses signal transduction in response to the activating factor IFN-gamma

The goal of this study was to investigate how bacterial LPS affects macroph age responsiveness to the activating factor IFN-gamma, Pretreatment of macr ophages with LPS for <2 h increased the transcriptional response to IFN- ga mma. In contrast, simultaneous stimulation with IFN-gamma and LPS, or pretr eatment with LPS for >4 h, suppressed Stat1 tyrosine 701 phosphorylation, d imerization, and transcriptional activity in response to IFN-gamma. Consist ently, the induction of MHCII protein by IFN-gamma was antagonized by LPS p retreatment. Neutralizing Abs to IL-10 were without effect on LPS-mediated suppression of Stat1 activation, Decreased IFN-gamma signal transduction af ter LPS treatment corresponded to a direct induction of suppressor of cytok ine signaling3 (SOCS3) mRNA and protein, Under the same conditions socs1, s ocs2, and cis genes were not transcribed. In transfection assays, SOCS3 was found to suppress the transcriptional response of macrophages to IFN-gamma . A causal link of decreased IFN-gamma signaling to SOCS3 induction was als o suggested by the LPS-dependent reduction of IFN-gamma-mediated Janus kina se 1 (JAK1) activation. Further consistent with inhibitory activity of SOCS 3, LPS also inhibited the JAK2-dependent activation of Stat5 by GM-CSP. Our results thus link the deactivating effect of chronic LPS exposure on macro phages with its ability to induce SOCS3.