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It has previously been reported by us that a brief prior exposure of mouse bone marrow culture-derived macrophages to bacterial lipopolysaccharide (LPS) resulted in a dramatic reduction in their ability to produce NO in response to a subsequent stimulus with either interferon-gamma (IFN-gamma) or IFN-gamma plus LPS. We show here that this brief exposure to LPS results in an impaired response to subsequently added IFN-gamma. A 2--4 h pretreatment with LPS leads to a dramatic reduction in the IFN-gamma-induced DNA-binding of the transcription factor, signal transducer and activator of transcription 1 alpha (STAT1 alpha). This loss in ability to activate STAT1 alpha temporally correlates with the LPS-induced accumulation of mRNA encoding the suppressor of cytokine signalling-1 (SOCS-1). However, LPS does not directly induce the synthesis of SOCS-1. Rather, LPS induces the synthesis of autocrine/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 production incompletely inhibits the induction of SOCS-1. We show that mouse IFN-beta directly induces the synthesis of SOCS-1, without the need for prior protein synthesis, and does so with faster kinetics than does LPS. Our results are consistent with the non-specific nature of LPS-induced tolerance and provide a mechanistic insight into nonspecificity; LPS indirectly induces the synthesis of a protein mediator, SOCS-1, which inhibits the signalling that is induced by IFN-gamma.

biochemical journal

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