Lactobacilli and Streptococci activate NF-kappa B and STAT signaling pathways in human macrophages

J Immunol. 2000 Apr 1;164(7):3733-40. doi: 10.4049/jimmunol.164.7.3733.

Abstract

Gram-positive bacteria induce the production of several cytokines in human leukocytes. The molecular mechanisms involved in Gram-positive bacteria-induced cytokine production have been poorly characterized. In this work we demonstrate that both nonpathogenic Lactobacillus rhamnosus GG and pathogenic Streptococcus pyogenes (group A streptococci) induce NF-kappa B and STAT DNA-binding activity in human primary macrophages as analyzed by EMSA. NF-kappa B activation was rapid and was not inhibited by a protein synthesis inhibitor cycloheximide, suggesting that these bacteria could directly activate NF-kappa B. STAT1, STAT3, and IFN regulatory factor-1 DNA binding was induced by both bacteria with delayed kinetics compared with NF-kappa B. In addition, streptococci induced the formation of IFN-alpha-specific transcription factor complex and IFN-stimulated gene factor-3 (ISGF3). STAT1 and STAT3 activation and ISGF3 complex formation were inhibited by cycloheximide or by neutralization with IFN-alpha/beta-specific Abs. Streptococci were more potent than lactobacilli in inducing STAT1, ISGF3, and IFN regulatory factor-1 DNA binding. Accordingly, only streptococci induced IFN-alpha production. The activation of the IFN-alpha signaling pathway by streptococci could play a role in the pathogenesis of these bacteria. These results indicate that extracellular Gram-positive bacteria activate transcription factors involved in cytokine signaling by two mechanisms: directly, leading to NF-kappa B activation, and indirectly via cytokines, leading to STAT activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites / immunology
  • Child
  • DNA / metabolism
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / biosynthesis
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • DNA-Binding Proteins / physiology
  • Humans
  • Immune Sera / pharmacology
  • Interferon Regulatory Factor-1
  • Interferon-Stimulated Gene Factor 3
  • Interferon-Stimulated Gene Factor 3, gamma Subunit
  • Interferon-alpha / biosynthesis
  • Interferon-alpha / immunology
  • Interleukin-6 / biosynthesis
  • Lactobacillus / drug effects
  • Lactobacillus / immunology*
  • Macrophages / drug effects
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Macrophages / microbiology*
  • NF-kappa B / metabolism*
  • NF-kappa B / physiology
  • Phosphoproteins / biosynthesis
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Protein Synthesis Inhibitors / pharmacology
  • RNA, Messenger / biosynthesis
  • STAT1 Transcription Factor
  • STAT3 Transcription Factor
  • Signal Transduction / drug effects
  • Signal Transduction / immunology*
  • Streptococcus pyogenes / drug effects
  • Streptococcus pyogenes / immunology*
  • Trans-Activators / antagonists & inhibitors
  • Trans-Activators / metabolism*
  • Trans-Activators / physiology
  • Transcription Factors / metabolism
  • Tumor Necrosis Factor-alpha / biosynthesis

Substances

  • DNA-Binding Proteins
  • IRF1 protein, human
  • IRF9 protein, human
  • Immune Sera
  • Interferon Regulatory Factor-1
  • Interferon-Stimulated Gene Factor 3
  • Interferon-Stimulated Gene Factor 3, gamma Subunit
  • Interferon-alpha
  • Interleukin-6
  • NF-kappa B
  • Phosphoproteins
  • Protein Synthesis Inhibitors
  • RNA, Messenger
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Trans-Activators
  • Transcription Factors
  • Tumor Necrosis Factor-alpha
  • DNA