ENDOTOXIN-INDUCED CYTOKINE GENE-EXPRESSION INVIVO .2. REGULATION OF TUMOR-NECROSIS-FACTOR AND INTERLEUKIN-1-ALPHA-BETA EXPRESSION AND SUPPRESSION

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  • 1 November 1990
    • journal article
    • research article
    • Vol. 137  (5) , 1173-1185
Abstract
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.degree., or 4.degree.C, 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, 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-1mRNA 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.

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