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Regulation of C4b-binding protein gene expression by the acute-phase mediators tumor necrosis factor-alpha,

G J Moffat1, B F Tack

  • 1Department of Immunology, Scripps Research Institute, La Jolla, California 92037.

Biochemistry
|December 15, 1992
PubMed

Insights

C4b-binding protein (C4BP) gene expression increases in the liver during acute inflammation. Cytokines like TNF-alpha and IL-6 induce C4BP transcription, while dexamethasone inhibits it, requiring protein synthesis.

Area of Science:

  • Immunology
  • Molecular Biology
  • Biochemistry

Background:

  • C4b-binding protein (C4BP) regulates the classical complement pathway.
  • Hepatic C4BP mRNA levels significantly increase during acute-phase responses in rodents.
  • C4BP gene expression during inflammation is primarily localized to the liver.

Purpose of the Study:

  • To investigate the molecular mechanisms regulating C4BP gene expression during the acute-phase response.
  • To identify the role of specific cytokines and signaling molecules in C4BP induction.
  • To determine the transcriptional regulation of C4BP gene expression.

Main Methods:

  • Utilized the rat hepatoma cell line FAO.
  • Administered cytokines: tumor necrosis factor-alpha (TNF-alpha), interleukin-1 alpha (IL-1 alpha), and interleukin-6 (IL-6).
  • Used dexamethasone, cycloheximide, and actinomycin D to assess regulatory pathways and transcriptional control.

Main Results:

  • TNF-alpha induced a 2.7-fold increase in C4BP mRNA levels in FAO cells.
  • Combined TNF-alpha, IL-1 alpha, and IL-6 showed synergistic 4-fold induction of C4BP mRNA.
  • Dexamethasone inhibited TNF-alpha-induced C4BP expression, and cycloheximide indicated a need for protein synthesis.
  • Rapid induction by TNF-alpha and IL-6, inhibited by actinomycin D, confirmed transcriptional regulation.
  • Identified the major transcriptional start site and putative response elements in the rat C4BP gene's 5' regulatory region.

Conclusions:

  • C4BP gene expression is transcriptionally regulated during the acute-phase response.
  • Cytokines TNF-alpha, IL-1 alpha, and IL-6 play key roles in inducing C4BP expression, with synergistic effects observed.
  • Glucocorticoids like dexamethasone can modulate this induction, highlighting complex regulatory networks.

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