Influenza A virus infection of macrophages. Enhanced tumor necrosis factor-alpha (TNF-alpha) gene expression and lipopolysaccharide-triggered TNF-alpha release.
We have previously shown that infection of macrophages by influenza A virus is capable of priming for a high TNF-alpha production in response to LPS. The present study was designed to examine in more detail TNF-alpha gene expression and TNF-alpha protein release of virus-infected, murine PU5-1.8 macrophages in the presence or absence of low and by itself rather inefficient concentrations of LPS (10 ng/ml). Although influenza A virus infection alone induced a massive TNF-alpha mRNA accumulation, translation into the bioactive TNF-alpha protein was low as intra- and extracellularly determined by bioassay, specific ELISA and Western blot. However, when LPS was added simultaneously or up to 4 h after infection, a high TNF-alpha production was initiated. The virus-induced TNF-alpha mRNA accumulation appeared to be due to both transcriptional and post-transcriptional changes: an enhanced TNF-alpha gene transcription as determined by nuclear run-on transcription assay and a markedly prolonged half-life of TNF-alpha mRNA as shown in actinomycin D-treated macrophages. These findings imply that influenza A virus may 1) either directly or indirectly stimulate TNF-alpha gene transcription activators or may interfere with labile transcription repressor proteins and 2) may stabilize TNF-alpha mRNA by delaying its degradation. Both mechanisms, taken together, prime influenza A virus-infected macrophages for a high TNF-alpha release in response to LPS which, as clinical cases show, may adversely affect patients with combined influenza A virus and bacterial infections.
Institute of Immunology, Philipps University, Marburg, Germany.
J H
JH
Gong
H
H
Sprenger
F
F
Hinder
A
A
Bender
A
A
Schmidt
S
S
Horch
M
M
Nain
D
D
Gemsa
D000818:Animals; D002460:Cell Line; D015870:Gene Expression; D066298:In Vitro Techniques; D009980:Influenza A virus / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D009976:Orthomyxoviridae Infections / Q000276:immunology*; D012333:RNA, Messenger / Q000378:metabolism; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism
D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha