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Infection and Immunity, April 1999, p. 1553-1559, Vol. 67, No. 4
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

NF-kappa B1 (p50) Is Upregulated in Lipopolysaccharide Tolerance and Can Block Tumor Necrosis Factor Gene Expression

Stefan Kastenbauer, and H. W. Löms Ziegler-Heitbrock*

Institute for Immunology, University of Munich, 80336 Munich, Germany

Received 10 November 1998/Returned for modification 10 December 1998/Accepted 12 January 1999

Monocytes respond to lipopolysaccharide (LPS) stimulation with a rapid expression of the tumor necrosis factor (TNF) gene. Upon repeated LPS stimulation there is, however, little production of TNF mRNA and protein; i.e., the cells are tolerant to LPS. Analysis of NF-kappa B proteins in gel shift assays demonstrated that the DNA binding activity that is induced by LPS stimulation in tolerant cells consists mainly of p50-p50 homodimers. Since p50 can bind to DNA but lacks a transactivation domain, this may explain the blockade of TNF gene expression. We now show that in the monocytic cell line Mono Mac 6, this inability to respond can be largely ascribed to NF-kappa B, since a reporter construct directed by a trimeric NF-kappa B motif is strongly transactivated by LPS stimulation of naive cells whereas LPS-tolerant cells exhibit only low activity. Also, Western blot analyses of proteins extracted from purified nuclei showed mobilization of threefold-higher levels of p50 protein in tolerant compared to naive cells, while mobilization of p65 was unaltered. Overexpression of p50 in HEK 293 cells resulted in a strong reduction of p65-driven TNF promoter activity at the levels of both luciferase mRNA and protein. These data support the concept that an upregulation of p50 is instrumental in LPS tolerance in human monocytes.

* Corresponding author. Mailing address: Institute for Immunology, University of Munich, Goethestr. 31, 80336 Munich, Germany. Phone: 49 89 5996 676. Fax: 49 89 5996 680. E-mail: ziegler{at}ifi.med.uni-muenchen.de.

Infection and Immunity, April 1999, p. 1553-1559, Vol. 67, No. 4
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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