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Blood, Vol. 94 No. 9 (November 1), 1999:
pp. 3141-3150
Myeloid Transcription Factor C/EBP Is Involved in the Positive
Regulation of Lactoferrin Gene Expression in Neutrophils
Walter Verbeek,
Julie Lekstrom-Himes,
Dorothy J. Park,
Pham
My-Chan Dang,
Peter T. Vuong,
Seji Kawano,
Bernard M. Babior,
Kleanthis Xanthopoulos, and
H. Phillip Koeffler
From the Division of Hematology/Oncology, the Department of Medicine,
Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA;
Clinical Gene Therapy Branch, National Institutes of Health, Bethesda,
MD; the Division of Biochemistry, the Department of Molecular and
Experimental Medicine, The Scripps Research Institute, La Jolla, CA;
and Aurora Biosciences Inc, San Diego, CA.
Targeted mutation of the myeloid transcription factor C/EBP in
mice results in gram-negative septic death at 3 to 5 months of age.
This study defines the underlying molecular defects in their terminal
granulocytic differentiation. The mRNA for the precursor protein of the
cathelin-related antimicrobial peptides was almost completely absent in
the bone marrow cells of C/EBP / mice. This finding may help
explain their susceptibility to gram-negative sepsis, because both are
bacteriocidal peptides with potent activity against gram-negative
bacteria. Superoxide production was found to be reduced in both
granulocytes and monocytes of C/EBP/ mice. While gp91 phox
protein levels were normal, p47phox protein levels were considerably
reduced in C/EBP / granulocytes/monocytes, possibly limiting
the assembly of the NADPH oxidase. In addition, expression of mRNA of
the secondary and tertiary granule proteins, lactoferrin and
gelatinase, were not detected, and levels of neutrophil collagenase
mRNA were reduced in bone marrow cells of the knock-out mice. The
murine lactoferrin promoter has a putative C/EBP site close to the
transcription start site. C/EBP bound to this site in
electromobility shift assay studies and mutation of this site abrogated
binding to it. A mutation in the C/EBP site reduced the activity of the
promoter by 35%. Furthermore, overexpression of C/EBP in U937 cells
increased the activity of the wild-type lactoferrin promoter by 3-fold.
In summary, our data implicate C/EBP as a critical factor of host
antimicrobial defense and suggests that it has a direct role as a
positive regulator of expression of lactoferrin in vivo.
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