(Journal of Leukocyte Biology. 2000;68:779-784.)
© 2000
by Society for Leukocyte Biology
Expression of mammalian defensin genes
Vicki Kaiser and
Gill Diamond
Department of Anatomy, Cell Biology and Injury Sciences, UMDNJ-New Jersey Medical School, Newark
Correspondence: Gill Diamond, Ph.D., Department of Anatomy, Cell Biology and Injury Sciences, UMDNJ-New Jersey Medical School, 185 South Orange Ave., Newark, NJ 07103. E-mail: gdiamond{at}umdnj.edu
 |
ABSTRACT
|
|---|
Antimicrobial peptides are a prevalent mechanism of host defense found
throughout nature. In mammals, defensins are among the most abundant of
these broad-spectrum antibiotics, and are expressed in epithelial and
hematopoietic cells. The defensin peptides are especially abundant in
neutrophils; however, gene expression is limited to the promyelocyte
stage. In epithelial cells, defensin genes are found as both
constitutively expressed and inducible. Induction has been observed
in vitro by stimulation with bacterial lipopolysaccharide
as well as inflammatory mediators. In vivo, up-regulation
of several defensin genes occurs in both infectious and inflammatory
states. Gene regulation occurs via signal transduction pathways common
to other innate immune responses, utilizing transcription factors such
as nuclear factor (NF)-
B and NF interleukin-6. Together, the data
suggest a broad-based innate host defense whereby potent antimicrobial
peptides are present to prevent initial colonization by pathogenic
microorganisms. In addition, the recognition of bacteria coupled with a
nascent inflammatory response can bolster this defense by a coordinated
up-regulation of the peptides.
Key Words: antimicrobial peptides • host defense • innate immunity
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INTRODUCTION
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Innate immunity provides an organism with a first line of host
defense against pathogenic microorganisms. As opposed to adaptive
immunity, this response is nonclonal, nonspecific, and ever present. In
addition to its constitutive quality, there is a rapid response whereby
components of innate immunity are produced after an initial challenge
by pathogens. Among the cells that make up the arsenal of innate
immunity are circulating phagocytic cells, such as neutrophils and
macrophages, in addition to cells that line the mucosal epithelium. One
common characteristic of cells from these two distinct lineages is the
production of antimicrobial peptides, which act as part of the
armamentarium of the cells to prevent microbial colonization. The
peptides in phagocytic cells act as part of the oxygen-independent
microbicidal pathway, whereas in epithelial cells, they are presumed to
be secreted into the extracellular environment to provide antimicrobial
activity. In both cases, the genes that encode these peptides can
either be constitutively expressed or induced by inflammatory mediators
and bacterial challenge. In this review, we will examine the gene
expression of one family of mammalian antimicrobial peptides, the
defensins. We will discuss their tissue-specific expression,
inducibility, and the genetic elements that regulate their expression.
Antimicrobial peptides can be divided into numerous categories based on
their primary and secondary structures but most of them maintain
certain common structural characteristics. These include a cationic
charge, due to arginine and lysine residues, and a greater ability to
interact with bacterial membranes, due to an over-representation of
hydrophobic amino acids. The peptides also exhibit a broad spectrum of
antimicrobial activity, often including both gram-positive and
gram-negative bacteria, fungi, and enveloped viruses. In addition,
antimicrobial peptides are frequently found in families, where a single
species may have numerous homologs expressed in the same cell type,
suggesting complementary or synergistic activities between homologs.
Lower organisms, such as amphibians and fish, express a variety of
linear antimicrobial peptides in their skin secretions
[1
, 2
]. These exhibit an amphipathic
-helical structure and are similar to insect peptides, which are
abundantly expressed in hemolymph [3; for reviews see ref. 4
].
Mammals, on the other hand, express a variety of peptide families at a
number of sites, and the most thoroughly studied family is that of the
defensins.
Defensins are cationic peptides, 20–40 amino acids in length,
containing six cysteines, which form three intramolecular disulfide
bonds. They are classified as -, ß-, or 
-defensins, based on
the relative positions of these disulfide bonds. -Defensins were
first isolated from rabbit alveolar macrophages [5
].
Subsequently, homologous peptides were discovered in the neutrophils of
most species examined. These peptides are characterized by the
maintenance of a six-cysteine consensus sequence as well as several
other highly conserved amino acids [6
7
8
9
]. They exhibit
antimicrobial activity in vitro against bacteria
[10
, 11
], fungi [11
], and
enveloped viruses [12
].
Homologous peptides were also found in the Paneth cells at the base of
the crypts of Lieberkuhn in human [13
], mouse
[14
], and rat [15
] small intestine. These
defensins, known as cryptdins, were the first indication that defensins
could be expressed in both epithelial and myeloid cells. As opposed to
the neutrophil defensins, which presumably function intracellularly,
the small intestinal defensins are secreted into the lumen of the crypt
[16
].
As part of a study to define antimicrobial host defense of the
mammalian airway, a basic, cysteine-rich peptide expressed in the
bovine tracheal epithelium was discovered [17
]. This
molecule, tracheal antimicrobial peptide (TAP), exhibited numerous
similarities to the -defensins, but did not maintain the strict
-defensin cysteine-motif. Shortly thereafter, 13 new peptides were
discovered in the bovine neutrophil, which also exhibited the same
six-cysteine motif as TAP [18
]. These discoveries
resulted in the creation of a second class of defensins called the
ß-defensins, and have now been identified alongside -defensins in
humans, mice, and rats [for review, see ref. 19
]. A recently
described third class of defensins, -defensins, exhibit a unique
structure that is apparently the result of posttranslational processing
[20
]. These cyclic 18-residue peptides are the ligation
product of two nine-residue peptides that are each encoded by a
truncated cDNA.
As with all antimicrobial peptides studied to date, defensins are
initially synthesized as larger precursors, which are processed to the
mature, active peptide. The precursor to defensins is made as an 87- to
94-residue peptide consisting of a hydrophobic leader sequence, a short
acidic propiece, followed by the mature sequence [21
].
The proregion appears to act in charge neutralization of the highly
cationic mature peptide, resulting in the inactivation of antimicrobial
activity until processing is complete. However, this maturation process
is specific for different defensin subtypes. Processing of the
neutrophil defensins occurs during granulogenesis [21
].
The active peptide is located in the granules of the mature neutrophil,
and alternative processing can occur, resulting in isoforms differing
in up to four additional amino acids on the amino terminus of the
mature peptide [18
, 22
]. In contrast, the
defensins of the small intestines are secreted as prepropeptides, and
the final activation processing step occurs in the lumen of the crypt.
In the mouse, the lumenal processing enzyme has been identified as the
matrix metalloproteinase matrilysin [23
]. No active
defensins were found in the intestinal crypts of matrilysin-deficient
mice, and these mice were predisposed to intestinal infection of orally
introduced bacteria.
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DEFENSIN GENE STRUCTURE
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The genes encoding all classes of defensins are localized to a
single chromosomal region in the human genome, 8p21-23. Their relative
locations suggest their evolution from a single precursor, and that
myeloid -defensin genes evolved from Paneth cell -defensin genes
by duplication and divergence [24
, 25
]. The
number of defensin genes on chromosome 8 appears to vary within the
population, suggesting that this provides a genetic component to
individual resistance to infection [26
].
The genes encoding the leukocyte -defensins are comprised of three
exons, with the first exon encoding a 5’ untranslated region. The
remaining - and ß-defensins have two exons, which are equivalent
to exons two and three of the leukocyte -defensins. The gene
structure of the ß-defensins indicates a second subdivision. One
subfamily, which includes human ß-defensin 2 (hBD2), has a relatively
small (2 kb) intron and is characterized by inducible expression in
epithelial cells (see below). The other subfamily, which includes human
ß-defensin 1 (hBD1), has a large intron (about 10 kb), and is
characterized by constitutive expression in a variety of cell types.
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DEFENSIN TISSUE EXPRESSION AND REGULATION
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Both - and ß-defensins are expressed in a variety of
epithelial tissues, which serve as primary microbial interface sites.
Tables 1
and 2
list several mammalian - and ß-defensins identified to date:
their tissue expression, inducibility, and regulatory elements. As can
be seen from the tables, primary sources of defensins are myeloid,
airway, and intestinal cells. Although multiple tissues may be listed
for some defensins, the highest levels of gene expression are usually
localized to one tissue type. For example, EBD has been identified in
several bovine tissues, but mRNA levels are highest in the small
intestines.
Both neutrophil and macrophage myeloid cells have served as rich
sources of defensins. Numerous defensins have been isolated at high
concentrations from membranous storage granules of neutrophils. The
four -defensins (HNP-1/-4), isolated from the azurophilic granules
of human neutrophils [6
, 11
], make up
approximately 5–10% of the protein in these cells
[27
]. The dense granules of the bovine neutrophils have
yielded 13 ß-defensins [18
]. Although defensin
proteins are present in the mature neutrophil, they are synthesized in
the promyelocyte [21
]. It is surprising to note that
mouse neutrophils are devoid of defensins [28
].
The airway is also a site of antimicrobial challenge as reflected in
the numerous ß-defensins isolated from cow (TAP) [17
],
human (hBD1 / 2) [29
, 30
], mouse (mBD-1,
-2, -3) [31
32
33
34
], and pig (pBD-1) [35
].
In vitro data indicate an active role for these proteins in
airway defense. For example, stimulation of cultured airway cells by
lipopolysaccharide (LPS), interleukin-1ß (IL-1ß), or tumor necrosis
factor (TNF-) results in increased mRNA levels of TAP
[36
37
38
], hBD2 [30
, 39
40
41
42
],
and mBD-2, -3 [32
, 34
]. The bovine
ß-defensin LAP is coordinately up-regulated with TAP but at much
lower levels [38
]. In contrast, hBD1 [41
,
43
], mBD-1 [31
, 33
,
44
], and pBD-1 [45
] mRNA levels are
unaffected by such inducers.
The correlative increase of defensin mRNA with bacterial stimulation is
not limited to in vitro data. An increase of defensin mRNA
in the presence of infection was detected by in situ
hybridization in several in vivo studies. Increased defensin
message was only detected in bovine intestinal tissue from cows testing
positive for Mycobacterium paratuberculosis
[46
]. Likewise, increased defensin message was detected
in lung tissue from mouse and a calf experimentally infected with
Pseudomonas aeruginosa [32
] or
Pasteurella haemolytica [46
], respectively.
LAP expression was also increased in bovine tongue tissue in areas of
inflammation but not in neighboring, normal tissue [47
].
Finally, elevated hBD2 protein levels were only found in the plasma of
patients with bacterial pneumonia [48
]. These data
provide increasing support for the role of defensins in preventing
microbial pathogenesis.
Expression of the defensins within the gastrointestinal tract,
specifically the small intestines, creates a unique situation. Here,
the environment is much different than the sterile conditions of the
lower lung and blood. Microbiota are an intrinsic part of the proper
functioning of the lower gastrointestinal tract. Therefore, inherent in
the role of the defensins is the prevention of bacterial colonization
within and translocation from the lumen without disturbing the balance
of the native flora. Enteric defensins have been characterized in
humans (HD-5/-6) [13
, 49
], mice (cryptdins)
[14
], rats (cryptdins) [15
], and cows
(EBD) [50
]. In cows, the mRNA of EBD has been detected
in high levels in the distal small intestines and colon; it is secreted
as an active peptide, and its mRNA is induced by inflammatory mediators
and microbial challenge. In contrast, humans, mice, and rats secrete
-defensins from crypt Paneth cells, which are then processed to an
active peptide. Microbial challenge raises lumenal cryptdin protein
levels by increasing Paneth cell secretions [51
], and
rat cryptdin mRNA levels are increased after hemorrhagic shock
[15
].
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DEFENSIN GENE REGULATION
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The observation that relative levels of defensin proteins differ
within the same and different tissues, and that some are inducible
while others are constitutive, suggests that defensin gene regulation
is important to the maintenance of a balanced spectrum of antimicrobial
activity. Therefore, the identification of the regulatory elements and
signaling pathways involved in defensin gene expression is of interest.
Studies have shown consistencies in the gene expression of both TAP and
the human homolog hBD2. For example, in vitro LPS induction
of both genes is mediated by the LPS co-receptor CD14 and results in an
increase of NF-B activity [36
, 52
]. In
addition, the 5’ flanking region of both these genes contain consensus
binding sites for the nuclear transcription factors NF-B and nuclear
factor interleukin 6 (NF IL-6) [37
, 53
].
In vitro studies, in which bovine tracheal epithelial cells
were transfected with reporter gene constructs, showed that both sites
are necessary for TAP gene induction upon stimulation with LPS
[37
]. In the same study, gel mobility shift assays
demonstrated that NF-B binding was induced upon LPS treatment,
whereas NF IL-6 binding was constitutive. However, the observation that
TAP gene expression in bovine alveolar macrophage is not induced by LPS
treatment suggests differences in tissue-specific regulation.
Differences from TAP are observed in the regulatory sites of two other
bovine ß-defensin genes. The intestinal gene EBD lacks sequences for
NF-B, yet has been shown to be induced [50
]. Like
TAP, EBD retains the NF IL-6 consensus sequences but also contains a
binding site for H-APF-1. It has been suggested that this factor
cooperates with NF IL-6 in gene activation [50
]. The
constitutively expressed neutrophil defensin BNBD-4 also lacks an
NF-B site but retains NF IL-6 consensus sequences
[54
]. In BNBD-4, the recognition sequence for the
myeloid-specific factor PEB2/CBF is also present, and this factor may
be important for its myeloid expression [54
].
Support of myeloid-specific regulation also comes from studies of the
regulatory sequences of the HNP-1 and -3 genes. The observation that
HNP-1 is more abundant in human neutrophils than HNP-3 suggests that
regulation of the two genes may differ. However, reporter constructs
transfected into human promyelocytic leukemia cells show that both
genes were equally expressed. Although not important to the
differential expression of the two genes, a CCAAT/enhancer-binding
protein site was important for gene expression. In addition, promoter
activities were very low in a nonhematopoietic cell line, suggesting
that HNP expression is myeloid-specific [55
]. Because
HNP-2 is a proteolytic cleavage product of HNP-1 and/or HNP-3, the
difference in the HNP-1/-3 protein levels was attributed to
differential protein cleavage and indicates another means of defensin
protein regulation.
|
ADDITIONAL ROLES FOR DEFENSINS
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The roles of defensins are not limited to antimicrobial activity.
Independent of their isolation and characterization as antimicrobial
peptides, some defensins are suppressors of ACTH activity on the
mammalian adrenal cortex [56
]. A similar inhibitory
effect is that of neutrophil defensins on tissue-type plasminogen
activator (tPA)-mediated fibrinolysis [57
]. This
inhibition may be part of the overall host defense function of
defensins, in that prevention of clot dissolution by tPA-mediated
fibrinolysis may better contain the inflammation associated with the
introduction of a pathogen. In addition, extracellular defensins, such
as hBD2, exhibit chemotactic activity for monocytes
[58
], immature dendritic cells (DC) [59
],
and T cells [60
], suggestive of a pro-inflammatory
activity. The chemotactic activity for DC and T cells appears to be
mediated through the CCR6 receptor [59
]. Defensins were
also observed to be mitogenic for fibroblasts [61
].
Together, these functions can be seen as a combined host defense system
by linking direct bactericidal activity with recruitment of
inflammatory cells and wound healing.
|
SUMMARY
|
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From gene structure to gene and tissue expression, it is evident
that many homologies exist between mammalian defensins. These
likenesses have been fundamental in uncovering new defensins from novel
tissues and animals. However, marked differences also exist and have
been reported in this review. Some defensins are constitutively
expressed, whereas others are inducible. Not all defensins are
expressed in all tissue types, and tissues that express numerous
defensins do not express them at equal levels. Some defensins are
inducible in one tissue type but not in another and yet some have roles
outside the scope of antimicrobial activity. These observations suggest
that the induction of defensin genes results in a myriad of effects,
not limited to direct antimicrobial activity, but whose ultimate goal
is the limitation of pathogenic infections. Analysis of tissue function
differences both within and between species can contribute to
understanding the molecular roles and evolutionary lineage of
defensins.
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ACKNOWLEDGEMENTS
|
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The authors thank Danielle Laube and Diana Legarda for their
helpful comments. G. D. was supported by grants from the National
Heart Lung and Blood Institute (HL56400) and the Cystic Fibrosis
Foundation (Diamon97P0).
Received August 13, 2000;
revised August 21, 2000;
accepted August 22, 2000.
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