A labile transcriptional repressor modulates endotoxin tolerance.
Tolerance to bacterial lipopolysaccharide (LPS, endotoxin) is an adaptive cellular process whereby exposure to endotoxin induces a subsequent hyporesponsive state characterized by decreased levels of LPS-induced cytokine mRNA and protein. We demonstrate, in a human promonocytic cell line, THP-1, that endotoxin tolerance is manifested by decreased LPS-induced interleukin 1 beta (IL-1 beta) transcription. Inhibition of protein synthesis reverses the tolerant phenotype by inducing transcription of IL-1 beta in the absence of a second stimulus. These results indicate that a labile protein contributes to the endotoxin-tolerant phenotype, and that this factor acts in a dominant repressive manner to inhibit the activity of existing transcription factors. We provide further data that cellular expression of I kappa B-alpha correlates with downregulated IL-1 beta gene expression during endotoxin tolerance, implicating I kappa B-alpha as a potential candidate for the labile repressor identified herein.
Department of Microbiology and Immunology, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina 27157.
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LaRue
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McCall
D015152:Blotting, Northern; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D004640:Emetine / Q000494:pharmacology; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis*; D007700:Kinetics; D008070:Lipopolysaccharides / Q000633:toxicity*; D011691:Puromycin / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D012097:Repressor Proteins / Q000096:biosynthesis*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D007375:Interleukin-1; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D012097:Repressor Proteins; D011691:Puromycin; D003513:Cycloheximide; D013755:Tetradecanoylphorbol Acetate; D004640:Emetine