Endotoxin tolerance: in vivo regulation of tumor necrosis factor and interleukin-1 synthesis is at the transcriptional level.
Endotoxin tolerance is associated with a decreased production of many inflammatory mediators following stimulus-induced desensitization. The mechanisms involved in the regulation of tumor necrosis factor (TNF) and interleukin-1 (IL-1) beta expression were investigated in peritoneal macrophages from endotoxin tolerant mice. The absence of a serum TNF peak in tolerant mice correlated with a significant reduction in both TNF and IL-1 beta mRNA accumulation in macrophages from these animals. The reduction in both IL-1 and TNF mRNA was consistent with a decrease in transcriptional activity by nuclear run-on assays for both cytokines and a reduced amount of the nuclear-associated transcription factor NF-KB. Therefore, the hyporesponsive state associated with endotoxin tolerance is characterized by transcriptional regulation of both TNF and IL-1 synthesis.
Zuckerman
S H
SH
Lilly Research Laboratories, Indianapolis, Indiana 46285.
Evans
G F
GF
D000818:Animals; D001483:Base Sequence; D004731:Endotoxins / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D007108:Immune Tolerance; D007375:Interleukin-1 / Q000096:biosynthesis / Q000235:genetics*; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000032:analysis; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics*
D004731:Endotoxins; D007375:Interleukin-1; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C044101:endotoxin, Escherichia coli