Endotoxin-induced cytokine gene expression in vivo. II. Regulation of tumor necrosis factor and interleukin-1 alpha/beta expression and suppression.
Tumor necrosis factor alpha (TNF alpha) mRNA is present in a preformed intracellular pool in the spleen, liver, and small bowel of naive rats. Endotoxin (Salmonella typhus lipopolysaccharide) injected intravenously induces little or no increase in whole-organ TNF mRNA levels at 15', 30', 1 degree, 2 degrees, or 4 degrees, whereas serum TNF levels are markedly elevated at 1 and 2 hours. Dexamethasone pretreatment of rats suppresses LPS-induced serum TNF concentrations, but does not suppress TNF mRNA levels in the spleen or bowel. Tachyphylaxis experiments demonstrate that a second injection of endotoxin 2 hours after an initial injection fails to induce a second peak of serum TNF, although TNF mRNA levels in the spleen and bowel remain at the levels found in naive rats. Corynebacterium parvum upregulates endotoxin-induced serum TNF release and intravenous injection of IL-1 induces the release of serum TNF but neither alters whole-organ TNF mRNA levels. Interleukin-1 alpha (IL-1 alpha) mRNA was not constitutively detected in whole-organ RNA preparations of the spleen, liver, and small bowel of naive rats. Endotoxin induces IL-1 alpha mRNA most easily appreciated in the spleen beginning at 1 hour, peaking at 2 to 4 hours, and disappearing by 6 hours. Interleukin-1 beta (IL-1 beta) mRNA was not constitutively detected in the organs examined or was present in small amounts. Endotoxin induces IL-1 beta mRNA beginning at 0.5 hours, peaking at 1 hour, and disappearing by 6 hours. Dexamethasone pretreatment prevents the LPS-induced appearance of IL-1 alpha mRNA and suppresses but does not completely inhibit the appearance of IL-1 beta mRNA. C. parvum upregulates endotoxin-induced IL-1 mRNA expression. Intravenous injection of TNF or IL-1 both induce IL-1 mRNA expression. In conclusion, TNF mRNA is constitutively expressed and TNF mRNA levels as analyzed in whole-organ RNA preparations do not change in concert with serum TNF protein levels during conditions of endotoxemia, dexamethasone treatment, tachyphylaxis, priming with C. parvum, or after injection of IL-1. In contrast, IL-1 mRNA expression during endotoxemia, dexamethasone treatment, priming with C. parvum, or after injection of TNF or IL-1 shows clear increases and decreases in whole-organ RNA preparations.
Ulich
T R
TR
Department of Pathology, University of California, Irvine School of Medicine 92717.
Guo
K Z
KZ
Irwin
B
B
Remick
D G
DG
Davatelis
G N
GN
D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology; D004731:Endotoxins / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D007375:Interleukin-1 / Q000235:genetics*; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008233:Lymphotoxin-alpha / Q000235:genetics*; D008297:Male; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011917:Rats, Inbred Lew; D012475:Salmonella; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D013489:Suppression, Genetic / Q000187:drug effects*; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D004731:Endotoxins; D007375:Interleukin-1; D008070:Lipopolysaccharides; D008233:Lymphotoxin-alpha; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone