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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online June 18, 2001 as doi:10.1096/fj.00-0865fje. |
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IPF PharmaCeuticals GmbH, 30625 Hannover, Germany; and
* Medizinische Klinik I, Grosshadern, Ludwig-Maximilians-Universität, 81377 Munich, Germany
2Correspondence: IPF PharmaCeuticals GmbH, Feodor-Lynen-Strasse 31, D-30625 Hannover, Germany. E-mail: wgforssmann{at}gmx.de
SPECIFIC AIMS
The aim of this study was to identify and characterize a novel human member of the ß-defensin family by screening genomic sequences, analyze its genomic structure, tissue distribution, and regulation, and evaluate its antimicrobial and chemoattractant activities.
PRINCIPAL FINDINGS
1. Analysis of the genomic and cDNA sequences of the novel
ß-defensin
To identify genomic sequences around human
ß-defensin 2 at the chromosomal region 8p23, the peptide sequence of
this ß-defensin was used to perform a ‘basic local alignment search
tool’ (BLAST) search in the High Throughput Genomic (HTG) division of
the GenBank. Accession numbers AF202031, AF252831, AF189745, and
AC074340 were found and subsequently screened for the presence of the
ß-defensin consensus pattern. Analysis of the clone AF202031 revealed
a genomic sequence coding for the carboxy-terminal region of a putative
novel ß-defensin, which was found in several HTG clones available at
GenBank and subsequently termed hBD-4. The full-length cDNA for hBD-4
could be generated by RACE-PCR, showing a 216 bp open reading frame
coding for a putative prepropeptide of 72 amino acids in
length
(MQRLVLLLAVSLLLYQDLPVRSEFELDRICGYGTARCRKKCRSQEYRIGRCPNTYACCLRKWDESLLNRTKP).
This peptide exhibited the presence of the
ß-defensin-specific pattern of six cysteine residues, although the
amino acid sequence identity with hBD-1, hBD-2, and hBD-3 was only
between 20 and 25%. The genomic sequence of hBD-4 shows the classical
structure of ß-defensins, with two exons separated by a 4495 bp
intron. While the first exon is encoding most of the signal peptide,
the second exon is encoding the end of the signal peptide and the
propeptide. Analysis of the 1200 bp upstream of the first exon revealed
a TATA boxless region and several AP-1 and GATA1 binding sites. No
NF-
B or STAT binding sites were found at the 5'-flanking region of
this gene.
2. hBD-4 exhibits a restricted pattern of expression
The distribution of hBD-4 transcripts in the human body
was evaluated by the highly sensitive real-time quantitative RT-PCR
(TaqMan) method. The highest hBD-4 expression was found in the testis.
Gastric antrum also exhibited relatively high levels. A lower and
constitutive hBD-4 expression was observed in uterus, neutrophils,
thyroid gland, lung, and kidney (Fig. 1A
). No detectable expression was found in any other tissues
tested.
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3. hBD-4 expression is induced by infection and phorbol
12-myristate 13-acetate (PMA) in lung epithelial cells
Since human ß-defensins have been described to be
either constitutively expressed or induced by infection or
inflammation, we further investigated the effect of infection on the
hBD-4 expression by real-time quantitative RT-PCR in human respiratory
epithelial cells isolated from large airways resected during surgery
and cultivated in air/liquid interface cultures. Basal hBD-4 mRNA
levels increased twofold upon addition of heat-inactivated
Pseudomonas aeruginosa, whereas 104
and 106 colony-forming units of P.
aeruginosa gave rise to 1.5-fold and 3.3-fold increases,
respectively, and 106 colony-forming units of
Streptococcus pneumoniae up-regulated the hBD-4 expression
by 7-fold (Fig. 1B
). We investigated which inflammatory
factors could be responsible for this up-regulation in SAEC 6043 small
airway epithelial cells. The low basal expression of hBD-4 did not
increase after 24 h exposure to either interleukin 1
(IL-1),
IL-6, interferon 
(IFN), or tumor necrosis factor (TNF-).
However, PMA treatment gave rise to a more than 60-fold increase in
hBD-4 mRNA levels. Analysis of the temporal pattern of this
up-regulation revealed that hBD-4 expression was not detectable after
30 min of PMA stimulation and reached a maximum after 12 h (Fig. 1C
).
4. hBD-4 is an endogenous salt-dependent antimicrobial
peptide that exhibits synergism with other antibiotics
To evaluate the antimicrobial activity of hBD-4, the
predicted biologically active peptide containing the
ß-defensin-specific pattern of three disulfide bonds was synthesized
by solid-phase chemistry. This hBD-4 peptide inhibited the growth of
gram-positive Staphylococcus carnosus TM300, gram-negative
Escherichia coli BL21, and yeast Saccharomyces
cerevisiae ATCC9763 in a conventional radial diffusion test (data
not shown).
The minimum hBD-4 concentration for growth inhibition (MIC) was further tested by conventional dilution assays with hBD-3, cathelicidin LL-37, and MBI 28 as positive controls. The MIC of hBD-4 was higher than 100 µg/ml for E. coli BL21, S. cerevisiae ATCC9763, Staphylococcus aureus ATCC25923, S. pneumoniae ATCC33400, and Burkholderia cepacia ATCC17770. In contrast, hBD-4 exhibited a strong antimicrobial activity against S. carnosus TM300 (4.5 µg/ml) and, in particular, against P. aeruginosa PAO1 (4.1 µg/ml).
The ability of hBD-4 to inhibit the growth of S. carnosus TM300 decreased 4-fold when the sodium chloride concentration was increased from 0 to 25 mM, 8-fold when it was increased to 50 mM, and more than 16-fold when it reached physiological concentrations (MIC>72 µg/ml).
Additional experiments were conducted to evaluate synergism between
hBD-4 and the endogenous antimicrobial peptides hBD-3 and lysozyme, an
antibiotic also present in the gastrointestinal and respiratory tract,
as well as the classical antibiotic ampicillin. Synergism was noted
with lysozyme (FIC<0.5) against S. carnosus TM300, whereas
an additive effect close to synergism (FIC
0.6) was observed with
hBD-3 for S. carnosus TM300 and E. coli BL21. A
combination of hBD-4 and ampicillin showed no interactions (FIC1).
5. hBD-4 is a chemoattractant for monocytes
The biological activity of hBD-4 was tested on cells involved in
the innate immune response for its chemotactic and
calcium-mobilizing properties. hBD-4 induced moderate migration of
monocytes, with a maximum response at 10 nM. The chemotactic activity
of hBD-4 was very similar in terms of potency and efficacy to that of
hBD-3. No migration by either hBD-4 or hBD-3 was observed for
neutrophils or eosinophils. Neither hBD-4 nor hBD-3 induced
Ca2 + mobilization, whereas fMLP or certain
chemokines elicited a transient rise of free cytosolic calcium in
monocytes, neutrophils, and eosinophils.
CONCLUSIONS AND SIGNIFICANCE
In this study, we report the discovery of the fourth human ß-defensin,
called hBD-4. The novel human ß-defensin was found by analysis of
genomic sequences mapping at chromosome 8p23, the gene locus where all
the known - and ß-defensins are clustered. hBD-4 exhibits the same
genomic organization as other ß-defensins, with two exons flanking an
intron of 4495 bp. The deduced prepropeptide exhibits a putative signal
peptide followed by the six-cysteine motif characteristic for a
ß-defensin. Finally, synthetic hBD-4 peptide demonstrated
antimicrobial activity against different bacteria and yeast and induced
migration of monocytes.
Like the sequences of mBD-3 and mBD-4, the spacing between the second and the third cysteine is reduced by one residue with respect to the sequences of hBD-1, hBD-2, and hBD-3. The sequence of hBD-4 also shows one amino acid less between the fourth and the fifth cysteine, confirming that the cysteine spacing may vary for other ß-defensins yet to be discovered. These differences in the primary structures may cause slightly different 3-dimensional structures. This could imply differential activities against the diverse classes of microorganisms that can infect the tissues where these ß-defensins are expressed.
Analysis of the promoter region of hBD-4 revealed no binding sites for
NF-B, an important inflammatory mediator, which are present in the
promoters of the inducible ß-defensins hBD-2, mBD-3, and TAP.
Moreover, no STAT binding site, recently associated with the
up-regulation of hBD-3 upon stimulation with IFN, was found in the
5'-flanking region of this gene. In agreement with these data, hBD-4
expression did not increase after stimulation by IL-1, IL-6,
IFN, or TNF-, but was increased more than 60-fold upon
stimulation with PMA. Bacterial infection (especially by S.
pneumoniae) and heat-inactivated P. aeruginosa also
up-regulated the hBD-4 gene. It is well known that PMA activates
specific protein kinase C (PKC) isoenzymes, and some are activated in
certain cell types in response to LPS and infection. Taken together,
these data suggest that the hBD-4 induction is mediated by PKC in
airway epithelial cells.
The highest hBD-4 expression was observed in the testis. These results agree with the relatively high levels of hBD-3 expression in the genital tract and may explain why bacterial testicular infections, in contrast to prostate infections, are extremely uncommon, although microbes can readily access male germ tissue through urethral entry. Unlike the other previously described human ß-defensins, hBD-4 expression is restricted to a few tissues. A restricted pattern is also exhibited by mBD-4. The selectivity in both expression pattern and antimicrobial activity suggests that hBD-4 is best suited to act at the epithelial locations where it is expressed.
We have also confirmed synergistic effects of hBD-4 with lysozyme as well as a strong additive effect with hBD-3. Since epithelial surfaces never express a single antimicrobial substance, but a mixture regulated by different mechanisms, their cooperative contribution to host defense is much more complex than just the sum of the activities of each individual molecule. The bactericidal activity of hBD-4 against P. aeruginosa was more than sixfold stronger than that for any other known ß-defensin. Together with the reinforcement of the antibiotic activity on interaction with other antimicrobial molecules and the chemotactic activity on monocytes, these data suggest an important role for this ß-defensin in innate immunity, especially in the respiratory tract. However, it has been reported that the antimicrobial potency of defensins might be inactivated in the high-salt environment of the cystic fibrosis airway surface fluid. The salt sensitivity of hBD-4 reinforces the concept of a putative role for these peptides in lung pathogenesis of cystic fibrosis, with obvious implications for therapeutic approaches. It is intriguing that an effective combination of hBD-4 and other endogenous antimicrobials engineered to overcome salt sensitivity may be administered into the airways of these patients, since the increasing resistance of microorganisms to classical antibiotics is a severe problem that requires the urgent development of new therapeutic approaches.SCHEME 1
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FOOTNOTES
1 To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.00-0865fje ; to cite this
article, use FASEB J. (June 18, 2001) 10.1096/fj.00-0865fje 
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 R. J. Jurevic, M. Bai, R. B. Chadwick, T. C. White, and B. A. Dale Single-Nucleotide Polymorphisms (SNPs) in Human {beta}-Defensin 1: High-Throughput SNP Assays and Association with Candida Carriage in Type I Diabetics and Nondiabetic Controls J. Clin. Microbiol., January 1, 2003; 41(1): 90 - 96. [Abstract] [Full Text] [PDF]
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M. Durr and A. Peschel Chemokines Meet Defensins: the Merging Concepts of Chemoattractants and Antimicrobial Peptides in Host Defense Infect. Immun., December 1, 2002; 70(12): 6515 - 6517. [Full Text] [PDF]
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J. Harder and J.-M. Schroder RNase 7, a Novel Innate Immune Defense Antimicrobial Protein of Healthy Human Skin J. Biol. Chem., November 22, 2002; 277(48): 46779 - 46784. [Abstract] [Full Text] [PDF]
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