Use of the acute phase serum amyloid A2 (SAA2) gene promoter in the analysis of pro- and anti-inflammatory mediators: differential kinetics of SAA2 promoter induction by IL-1 beta and TNF-alpha compared to IL-6

J Immunol Methods. 1997 Apr 25;203(2):123-30. doi: 10.1016/s0022-1759(96)00220-7.

Abstract

A cytokine responsive construct, pGL2-SAA2pt, was generated by cloning the acute phase promoter of human serum amyloid A2 (SAA2) upstream of a luciferase reporter gene. The construct responds to the inflammatory mediators MoCM, IL-1 beta, TNF-alpha, and IL-6 in a manner that closely mimics the response of the endogenous SAA2 gene to such stimuli: i.e. single treatments induce transcriptional activation by IL-1 beta and TNF-alpha to a greater extent than by IL-6 at 12-24 h. However, timecourse experiments show that the kinetics of induction generated by IL-1 beta and TNF-alpha are quite distinct from IL-6, IL-6 having a much greater effect at 3-6 h. IL-1 beta and TNF-alpha synergize with IL-6 to give a 10-fold increase in transcriptional readout over single cytokine treatments. The kinetics of this synergistic response resembles that generated by IL-6 alone. The IL-1 receptor antagonist, hIL-1ra, can specifically block the IL-1 beta driven transcriptional activation of pGL2-SAA2pt, but not that driven by TNF-alpha or IL-6. Furthermore, in synergistic cytokine combinations, it blocks only the IL-1 beta driven component indicating that the effect is biological and not attributable to toxicity. Consequently assays utilizing pGL2-SAA2pt will be useful both for the investigation of the kinetics of inflammatory signalling in a cytokine specific manner, and for the evaluation of the pro- and anti-inflammatory properties of novel natural and synthetic molecules.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute-Phase Proteins / drug effects
  • Acute-Phase Proteins / genetics*
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Base Sequence
  • Cells, Cultured
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / immunology
  • Humans
  • Inflammation Mediators / agonists
  • Inflammation Mediators / antagonists & inhibitors
  • Inflammation Mediators / pharmacology*
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1 / agonists
  • Interleukin-1 / pharmacology*
  • Interleukin-6 / agonists
  • Interleukin-6 / pharmacology*
  • Kinetics
  • Molecular Sequence Data
  • Promoter Regions, Genetic / drug effects
  • Promoter Regions, Genetic / immunology*
  • Receptors, Interleukin-1 / antagonists & inhibitors
  • Serum Amyloid A Protein / drug effects
  • Serum Amyloid A Protein / genetics*
  • Sialoglycoproteins / pharmacology
  • Transcription, Genetic / drug effects
  • Tumor Necrosis Factor-alpha / agonists
  • Tumor Necrosis Factor-alpha / pharmacology*

Substances

  • Acute-Phase Proteins
  • Anti-Inflammatory Agents, Non-Steroidal
  • IL1RN protein, human
  • Inflammation Mediators
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1
  • Interleukin-6
  • Receptors, Interleukin-1
  • Serum Amyloid A Protein
  • Sialoglycoproteins
  • Tumor Necrosis Factor-alpha