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.