Beutler perhaps knows Dr. Giroir???
Bruce A. Beutler, M.D.
Professor of Internal Medicine
Biochemistry and Molecular Biology
Office: 214-648-5006
FAX: 214-648-6395
Email: beutler@howie.swmed.edu
Innate immunity is largely dependent upon the actions of macrophages and NK cells, which seem capable of sensing host
invasion in a rather non-specific fashion. Unlike lymphocytes, which depend upon a huge array of highly specific
receptors, macrophages utilize a much smaller array of molecules that are rather flexible in their ability to detect microbial
pathogens. Far less is known about these broadly active receptor systems. However, it is clear that they are able to
recognize whole categories of micro-organisms. A case in point is the detection of gram negative bacteria, which are, as a
group, united in their ability to synthesize lipopolysaccharide (LPS), or endotoxin. LPS is a highly toxic molecule,
prompting massive release of toxic cytokines from macrophages. In large part, is thought to be responsible for the shock
syndrome that develops in the course of a serious gram negative infection. While LPS binds to macrophages via CD14, it
is not known how the the LPS signal traverses the cell membrane. In mice, a single codominant mutation (Lpsd) can
abolish all responses to LPS. Mice homozygous for the Lpsd allele are highly resistant to the lethal effect of LPS;
however, they are very susceptible to gram negative infection. Our laboratory is attempting to clone the Lps gene
through a positional approach. The location of the mutation has been narrowed to an interval well beneath 1 megabase in
size, and a number of candidate genes are being closely examined for evidence of a genetic lesion. It is believed that
isolation of the Lps gene will permit far more detailed understanding of the mechanisms of LPS signal transduction.
Conceivably, the protein encoded by Lps will itself be a target for the design of drugs that block endotoxin signaling.
Further, it is likely that variability in human susceptibility to endotoxic shock may be determined by polymorphism at this
locus.
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Kruys V, Thompson P and Beutler B (1993) Extinction of the TNF locus, and of genes encoding the LPS signaling
pathway. J Exp Med 177:1383-1390
Beutler B and Brown T (1993) Polymorphism of the mouse TNFa locus: sequence studies of the 3'UTR and first intron.
Gene 129:279-283
Kolls J, Peppel K, Silva M and Beutler B (1994) Prolonged and effective blockade of TNF activity through
adenovirus-mediated gene transfer. Proc Natl Acad Sci 91:215-219
Bazzoni F, Kruys V, Shakhov A, Jongeneel CV and Beutler B (1994) Analysis of TNF promoter responses to ultraviolet
light. J Clin Invest 93:56-62
Geppert TD, Whitehurst CE, Thompson P, and Beutler B (1994) LPS signals activation of TNF biosynthesis through
the RAS/RAF-1/MEK/MAPK pathway. Mol Med 1:93-103
Bazzoni F, Alejos E, and Beutler B (1995) Chimeric TNF receptors with constitutive signalling activity. Proc Natl Acad
Sci 92:5376-5380
Bazzoni F and Beutler B (1996) The tumor necrosis factor ligand and receptor families. N Engl J Med 334:1717-1725
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