Mechanisms of allergy and clinical immunology
Association between CD14 polymorphisms and serum soluble CD14 levels: Effect of atopy and endotoxin inhalation

https://doi.org/10.1016/j.jaci.2007.08.050Get rights and content

Background

A prerequisite for activation of the innate immune response by endotoxin is its binding to CD14.

Objective

The aim of this study was to evaluate the role of CD14 polymorphisms, atopy, and inhaled endotoxin in modulating serum CD14 levels.

Methods

Healthy volunteers (n = 88) were genotyped for CD14 polymorphisms at the −1619, −1359, and −159 loci, relative to the transcription start site. Subjects inhaled 20 μg of endotoxin, and white blood cell, C-reactive protein, LPS-binding protein, and soluble CD14 (sCD14) levels were measured before and after exposure.

Results

Homozygotes for the −1619G, −1359G, and −159T alleles had higher baseline levels of sCD14 than carriers of the CD14/−1619AA (P = .015), −1359GT/TT (P = .015), or −159CC (P = 0.017) genotypes. sCD14 levels increased within 24 hours of endotoxin inhalation (P < .0001 for all biomarkers); however, the association between CD14 polymorphisms and sCD14 levels was no longer present after exposure. The atopic status of an individual did not alter these associations. CD14 polymorphisms were not associated with levels of white blood cells, C-reactive protein, and LPS-binding protein before or after endotoxin challenge.

Conclusion

These data suggest that CD14 promoter polymorphisms and inhaled endotoxin modulate sCD14 levels.

Section snippets

Study population

Volunteer subjects were recruited from Brussels, Belgium, and were healthy nonsmoking adults between the ages of approximately 18 and 60 years. All subjects were nonasthmatic and free from regular use of medication. The Free University of Brussels and the University of Arizona Institutional Review Boards approved the study. Written informed consent was obtained from all subjects.

Endotoxin challenge

Subjects were exposed to 20 μg of endotoxin by means of inhalation, as described by Michel et al.4 Briefly, purified

LD and haplotype structure of the CD14 proximal promoter

The following SNPs were genotyped in the cohort: −1619, −1359, and −159 relative to the transcription start site or −1720, −1460, and −260 relative to the translation start site. All of these polymorphisms had a minor allele frequency of greater than 10% (CD14/−1619A→G = 0.455; CD14/−1359G→T = 0.262; CD14/−159T→C = 0.472) and were similar in frequency to the European American reference population used for the Program in Genomic Applications (http://innateimmunity.net). The genotype frequencies

Discussion

In 1990, Wright et al10 first described CD14 as a receptor involved in the recognition of LPS and other bacterial wall components. It was not until 1999 that an association between CD14 polymorphisms and sCD14 levels was described.16 Baldini et al16 found that CD14/−159TT homozygotes had significantly higher sCD14 levels than did carriers of the CC and CT genotypes. Although several studies have confirmed this association between various CD14 polymorphisms and sCD14 levels,17, 18, 25, 26, 27, 28

References (47)

  • R. Rylander

    Endotoxin in the environment—exposure and effects

    J Endotoxin Res

    (2002)
  • O. Michel et al.

    Domestic endotoxin exposure and clinical severity of asthma

    Clin Exp Allergy

    (1991)
  • O. Michel et al.

    Dose-response relationship to inhaled endotoxin in normal subjects

    Am J Respir Crit Care Med

    (1997)
  • O. Michel et al.

    Blood inflammatory response to inhaled endotoxin in normal subjects

    Clin Exp Allergy

    (1995)
  • J.A. Nightingale et al.

    Effect of inhaled endotoxin on induced sputum in normal, atopic, and atopic asthmatic subjects

    Thorax

    (1998)
  • J.N. Kline et al.

    Variable airway responsiveness to inhaled lipopolysaccharide

    Am J Respir Crit Care Med

    (1999)
  • N.C. Arbour et al.

    TLR4 mutations are associated with endotoxin hyporesponsiveness in humans

    Nat Genet

    (2000)
  • A. Poltorak et al.

    Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene

    Science

    (1998)
  • S.D. Wright et al.

    CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein

    Science

    (1990)
  • R. Medzhitov et al.

    Innate immune recognition: mechanisms and pathways

    Immunol Rev

    (2000)
  • Martinez F. Innate Immunity PGA, NHLBI Program Applications. Available at:...
  • M. Baldini et al.

    A polymorphism∗ in the 5′ flanking region of the CD14 gene is associated with circulating soluble CD14 levels and with total serum immunoglobulin E

    Am J Respir Cell Mol Biol

    (1999)
  • S. Guerra et al.

    The differential effect of genetic variation on soluble CD14 levels in human plasma and milk

    Am J Reprod Immunol

    (2004)

    • Cited by (0)

    Supported by grants from the National Institutes of Health (ES-00386 to T.D.L. and HL61892 to F.D.M.), the American Heart Association (9960342Z to T.D.L.), and Astra Zeneca Belgium (to O.M.).

    Disclosure of potential conflict of interest: F. D. Martinez has consulting arrangements with Genentech, GlaxoSmithKline, and Pfizer; has patent licensing arrangements with the CARE Network of the National Heart, Lung, and Blood Institute; and is on the advisory board for Merck. The rest of the authors have declared that they have no conflict of interest.

    ∗

    These authors contributed equally to this manuscript.

    View full text
    Copyright © 2008 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.