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 (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.
Crespo
A
A
Wilkinson Laboratory of the Kansas Cancer Institute and the Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, 1008 WHW, 3901 Rainbow Boulevard, Kansas City, KS 66160-7184, USA.
Filla
M B
MB
Russell
S W
SW
Murphy
W J
WJ
D000818:Animals; D015152:Blotting, Northern; D001854:Bone Marrow Cells / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D016898:Interferon-alpha / Q000502:physiology*; D016899:Interferon-beta / Q000502:physiology*; D007700:Kinetics; D008070:Lipopolysaccharides / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D013997:Time Factors
D002352:Carrier Proteins; D016898:Interferon-alpha; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D012097:Repressor Proteins; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D016899:Interferon-beta