Lipopolysaccharide-Binding Protein Critically Regulates Lipopolysaccharide-Induced IFN-β Signaling Pathway in Human Monocytes

Atsushi Kato, Takahisa Ogasawara, Toshiki Homma, Hirohisa Saito, Kenji Matsumoto*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

Abstract

LPS binding to Toll-like receptor 4 induces a large number of genes through activation of NF-κB and IFN-regulatory factor-3 (IRF-3). However, no previous reports have tested the role of serum proteins in LPS-induced gene expression profiles. To investigate how serum proteins affect LPS-induced signaling, we investigated LPS-inducible genes in PBMC using an oligonucleotide probe-array system. Approximately 120 genes up-regulated by LPS were hierarchically divided into two clusters. Induction of one cluster, containing only IFN-inducible genes, was serum dependent. Real-time PCR analysis confirmed that IFN-inducible genes were induced only in the presence of serum, whereas inflammatory genes were induced both in the presence and absence of serum. Further analysis demonstrated that addition of LPS-binding protein (LBP), but not of soluble CD14 to the serum-free medium enabled the induction of IFN-inducible genes and IFN-β itself by LPS in human monocytes. The mRNAs for IFN-β and EFN-inducible genes were induced by LPS only in the presence of serum from LBP+/+ mice, and not in the presence of serum from LBP-/- mice. Blocking experiments also confirmed the involvement of LBP in this phenomenon. Immunoblotting analysis showed that phosphorylation of c-Jun N-terminal kinase, p38, IRF-3, tyrosine kinase 2, and STAT1 by LPS, but not of NF-κB and extracellular signal-regulated kinase was abrogated in the absence of LBP. This critical role for LBP implies the presence of possible mechanisms linking LBP to the intracellular signaling between Toll-like receptor 4 and IRF-3, leading to the induction of IFN-β by LPS.

Original languageEnglish (US)
Pages (from-to)6185-6194
Number of pages10
JournalJournal of Immunology
Volume172
Issue number10
DOIs
StatePublished - May 15 2004

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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