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Tumor Necrosis Factor and Interleukin-1 Regulation by Lipopolysaccharide Pretreatment

Susan C. Seatter, MD; Terriel Bennet, MS; Mary H. Li, MD; Melvin P. Bubrick, MD; Michael A. West, MD, PhD

Arch Surg. 1994;129(12):1263-1270.

Abstract
Objective
To correlate cytokine gene expression with the release of protein product by murine peritoneal macrophages rendered tolerant by sequential endotoxin stimulation in vitro.

Design
In vitro investigation of the regulation of endotoxin-stimulated cytokine production following endotoxin pretreatment using cytokine bioassays, polymerase chain reaction, and Northern blot analyses.

Setting
In vitro cell culture model of sequential endotoxin stimulation of murine macrophages.

Interventions
Macrophages were pretreated with 0 or 100 ng/mL of lipopolysaccharide (LPS₁) for 24 hours and then stimulated with 0 or 100 ng/mL of LPS (LPS₂) for 4 or 24 hours. After stimulation, supernatant tumor necrosis factor (TNF) and interleukin-1 (IL-1) levels were measured by bioassay. Total RNA was extracted and messenger RNA (mRNA) corresponding to TNF and IL-1 was amplifed by reverse transcription-polymerase chain reaction or analyzed by Northern blot.

Results
Endotoxin pretreatment resulted in the augmentation of IL-1 (mean±SD, 78±9 vs 596±42 pg/mL, P<.01) and the inhibition of TNF (274±63 vs 61±3 pg/mL, P<.01) release 4 hours after stimulation with 100 ng/mL of LPS₂. A similar pattern of cytokine release was observed 24 hours after LPS₂ stimulation. Pretreatment produced an increased IL-1 message in response to 100 ng/mL of LPS₂. The TNF message was detectable in all groups receiving LPS₂ alone, but the highest levels of TNF mRNA were seen in LPS₁-pretreated cells stimulated with LPS₂.

Conclusions
Endotoxin pretreatment produced increased IL-1 message that paralleled the augmentation of IL-1 protein, whereas abundant TNF message was present even though TNF protein release was significantly inhibited. In this model of in vitro endotoxin tolerance, pretreatment initiates divergent pathways of cytokine regulation.

(Arch Surg. 1994;129:1263-1270)

Author Affiliations
From the Laboratory of Surgical Cell Biology and Metabolism, Department of Surgery, Hennepin County Medical Center, University of Minnesota, Minneapolis.

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