IFN-gamma and lipopolysaccharide differentially modulate expression of tumor necrosis factor receptor mRNA in murine peritoneal macrophages.
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.
Tannenbaum
C S
CS
Department of Immunology, Cleveland Clinic Foundation, OH 44195.
Major
J A
JA
Hamilton
T A
TA
D000818:Animals; D015342:DNA Probes; D018076:DNA, Complementary / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000145:classification / Q000235:genetics*; D011994:Recombinant Proteins
D015342:DNA Probes; D018076:DNA, Complementary; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D007371:Interferon-gamma