Indirect induction of suppressor of cytokine signalling-1 in macrophages stimulated with bacterial lipopolysaccharide: partial role of autocrine/paracrine interferon-alpha/beta

It has previously been reported by us that a brief prior exposure of mouse bone marrow culture-derived macrophages to bacterial lipopolysaccharide (LP S) resulted in a dramatic reduction in their ability to produce NO in respo nse to a subsequent stimulus with either interferon-gamma (IFN-gamma) or IF N-gamma plus LPS, We show here that this brief exposure to LPS results in a n impaired response to subsequently added IFN-gamma. A 2-4 h pretreatment w ith LPS leads to a dramatic reduction in the IFN-gamma-induced DNA-binding of the transcription factor, signal transducer and activator of transcripti on 1 alpha (STAT1 alpha). This loss in ability to activate STAT1 alpha temp orally correlates with the LPS-induced accumulation of mRNA encoding the su ppressor of cytokine signalling-1 (SOCS-1). However, LPS does not directly induce the synthesis of SOCS-1, Rather, LPS induces the synthesis of autocr ine/paracrine factors that are the true mediators of SOCS-1 induction. IFN- alpha/beta is one of these mediators, but plays only a partial role in the induction of SOCS-1 because neutralization of LPS-induced IFN-alpha/beta pr oduction incompletely inhibits the induction of SOCS-1. We show that mouse IFN-beta directly induces the synthesis of SOCS-1, without the need for pri or protein synthesis, and does so with faster kinetics than does LPS. Our r esults are consistent with the non-specific nature of LPS-induced tolerance and provide a mechanistic insight into nonspecificity; LPS indirectly indu ces the synthesis of a protein mediator, SOCS-1, which inhibits the signall ing that is induced by IFN-gamma.