A labile transcriptional repressor modulates endotoxin tolerance

doi:10.1084/jem.180.6.2269

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A labile transcriptional repressor modulates endotoxin tolerance

KE LaRue and CE McCall
Department of Microbiology and Immunology, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina 27157.

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.
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