IFN-gamma and lipopolysaccharide differentially modulate expression of tumor necrosis factor receptor mRNA in murine peritoneal macrophages

J Immunol. 1993 Dec 15;151(12):6833-9.

Abstract

Expression of TNF receptor (TNFR) mRNA has been examined in murine peritoneal macrophages stimulated with LPS and/or IFN-gamma. LPS markedly enhanced expression of a heterogenous population of mRNA, which hybridized with a cDNA encoding the type II TNFR. mRNA expression was optimally induced by 4 to 8 h and returned to baseline by 24 h after stimulation. Interestingly, though IFN-gamma can synergize with LPS for the expression of TNF-alpha, it abrogated the LPS-mediated enhancement of type II TNFR in a dose-dependent fashion. IFN-alpha, though less effective, had a qualitatively comparable effect. These effects were selective for the type II TNFR because levels of mRNA encoding the type I TNFR did not vary appreciably with any of the treatments described. The effects of IFN-gamma on LPS-mediated TNFR expression were dependent on the sequence of exposure; pretreatment with IFN-gamma was most effective at blocking response to LPS, whereas IFN-gamma added 1 h after initiation of LPS treatment had little or no effect. The effects of both LPS and IFN-gamma on type II TNFR expression were mediated at least in part by modulation of transcription. The effects of both LPS and IFN-gamma were also independent of protein synthesis because inclusion of cycloheximide in the treatment protocol did not abrogate either the inductive or the suppressive effects. These findings suggest that IFN-gamma and LPS modulate the physiologic action of TNF through complex mechanisms involving effects on the transcription of TNF-alpha itself and on receptors through which it may act in autocrine or paracrine fashion.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • DNA Probes
  • DNA, Complementary / genetics
  • Gene Expression Regulation / drug effects
  • Interferon-gamma / pharmacology
  • Lipopolysaccharides / pharmacology
  • Macrophages / immunology*
  • Macrophages / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • RNA, Messenger / genetics*
  • RNA, Messenger / metabolism*
  • Receptors, Tumor Necrosis Factor / classification
  • Receptors, Tumor Necrosis Factor / genetics*
  • Recombinant Proteins

Substances

  • DNA Probes
  • DNA, Complementary
  • Lipopolysaccharides
  • RNA, Messenger
  • Receptors, Tumor Necrosis Factor
  • Recombinant Proteins
  • Interferon-gamma