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

D Stoiber, P Kovarik, S Cohney, J A Johnston, P Steinlein, T Decker

Research output: Journal article (peer-reviewed)Journal article

229 Citations (Scopus)

Abstract

The goal of this study was to investigate how bacterial LPS affects macrophage responsiveness to the activating factor IFN-gamma. Pretreatment of macrophages with LPS for <2 h increased the transcriptional response to IFN-gamma. In contrast, simultaneous stimulation with IFN-gamma and LPS, or pretreatment with LPS for >4 h, suppressed Stat1 tyrosine 701 phosphorylation, dimerization, and transcriptional activity in response to IFN-gamma. Consistently, the induction of MHCII protein by IFN-gamma was antagonized by LPS pretreatment. Neutralizing Abs to IL-10 were without effect on LPS-mediated suppression of Stat1 activation. Decreased IFN-gamma signal transduction after LPS treatment corresponded to a direct induction of suppressor of cytokine signaling3 (SOCS3) mRNA and protein. Under the same conditions socs1, socs2, 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 also suggested by the LPS-dependent reduction of IFN-gamma-mediated Janus kinase 1 (JAK1) activation. Further consistent with inhibitory activity of SOCS3, LPS also inhibited the JAK2-dependent activation of Stat5 by GM-CSF. Our results thus link the deactivating effect of chronic LPS exposure on macrophages with its ability to induce SOCS3.

Original languageEnglish
Pages (from-to)2640-7
Number of pages8
JournalJournal of Immunology
Volume163
Issue number5
Publication statusPublished - 01 Sept 1999
Externally publishedYes

Keywords

  • Animals
  • Cell Line
  • Cell Line, Transformed
  • DNA-Binding Proteins/antagonists & inhibitors
  • Gene Expression Regulation/immunology
  • Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors
  • Humans
  • Interferon-gamma/physiology
  • Janus Kinase 1
  • Lipopolysaccharides/pharmacology
  • Macrophages/enzymology
  • Mice
  • Phosphorylation
  • Protein Biosynthesis
  • Protein-Tyrosine Kinases/antagonists & inhibitors
  • Proteins/genetics
  • Repressor Proteins
  • STAT1 Transcription Factor
  • Signal Transduction/immunology
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Time Factors
  • Trans-Activators/antagonists & inhibitors
  • Transcription Factors
  • Transfection
  • Tyrosine/metabolism

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