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,
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Arizona Respiratory Center and the Departments of
Pharmacology,
Medicine,
Pediatrics, and
¶ Cell Biology and Anatomy, College of Medicine, University of Arizona, Tucson, AZ 85724; and
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Molecular Immunology Section, Children’s Hospital Research Foundation, University of Cincinnati, Cincinnati, OH, 45229
CD14 is a pattern recognition receptor that plays a central role in
innate immunity through recognition of bacterial lipoglycans, primarily
LPS. Recently, our group has identified a common single nucleotide
polymorphism, -159C
T, in the CD14 proximal
promoter. Homozygous carriers of the T allele have a significant
increase in soluble CD14, but a decreased total serum IgE. This
epidemiologic evidence led us to investigate the molecular basis for
the effects of CD14/-159CT on CD14
regulation in monocytes and hepatocytes, the two major cell types known
to express this gene in vivo. EMSA analysis showed that the
T allele results in decreased affinity of DNA/protein
interactions at a GC box that contains a binding site for Sp1, Sp2, and
Sp3 transcription factors. In reporter assays, the transcriptional
activity of the T allele was increased in monocytic Mono
Mac 6 cells, which express low levels of Sp3, a member of the Sp family
with inhibitory potential relative to activating Sp1 and Sp2. By
contrast, both alleles were transcribed equivalently in Sp3-rich
hepatocytic HepG2 cells. Our data indicate that the interplay between
CD14 promoter affinity and the [Sp3]:[Sp1 + Sp2] ratio
plays a critical mechanistic role in regulating transcription of the
two CD14 alleles. Variation in a key gene of innate
immunity may be important for the pathogenesis of allergy and
inflammatory disease through gene-by-gene and/or gene-by-environment
interactions.
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