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7599.Ganz T. - Defensins (2000).pdf

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Tomas Ganz*
Medicine and Pathology, School of Medicine, University of California, Los Angeles,
10833 Le Conte Ave., Los Angeles, CA 90095-1690, USA
* corresponding author tel: 310 825 6112, fax: 310 206 8766, e-mail:
DOI: 10.1006/rwcy.2000.12006.
Defensins are a family of variably cationic 3�kDa
peptides with a conserved motif of six disulfide-linked
cysteines. They are expressed in host defense settings
(in phagocytes and epithelia) and display a broad
spectrum of antimicrobial activity. The production of
many defensins is constitutive but others are induced
by infectious or inflammatory stimuli. Some defensins
are chemoattractant for monocytes, lymphocytes, and
dendritic cells.
Defensins were discovered during a search for antimicrobial substances in human and animal phagocytes.
The class designation, purification, antimicrobial
characteristics (Ganz et al., 1985) and amino acid
sequences (Selsted et al., 1985a) of three human
neutrophil defensins were reported in 1985. Although
rabbit and guinea pig peptides that in retrospect
belonged to the same peptide family were first identified more than two decades earlier (Zeya and
Spitznagel, 1963, 1966) their structural characterization had to await improved technologies (Selsted
et al., 1983, 1985c; Selsted and Harwig, 1987). Since
then, additional defensins have been found in polymorphonuclear leukocytes of chickens (Harwig et al.,
1994), turkeys (Evans et al., 1994), rats (Eisenhauer
et al., 1989), and hamsters (Mak et al., 1996) but were
absent from the polymorphonuclear leukocytes of mice
(Eisenhauer and Lehrer, 1992).
Defensins produced by Paneth cells, specialized
intestinal epithelial cells, were first identified as a class
of abundant developmentally regulated mRNAs in
the mouse small intestine (Ouellette and Lualdi, 1990).
Human Paneth cell defensins were discovered by
cDNA and gene cloning based on homology to the
human neutrophil defensins (Jones and Bevins, 1992,
1993). The first -defensins were found by fractionation of bovine tracheal mucosa (Diamond et al., 1991)
and bovine neutrophils (Selsted et al., 1993). The two
known human epithelial -defensins were discovered
by a systematic search for novel peptides in human
hemofiltrate (Bensch et al., 1995) and in inflamed
human skin (Harder et al., 1997). Most recently
discovered epithelial defensins include -defensins in
sheep (Huttner et al., 1998), pigs (Zhang et al., 1998),
rhesus monkeys, rats, and mice (Huttner et al., 1997).
The name defensin is also used for peptides of similar
structure and function in plants (Broekaert et al.,
1995) and invertebrates (Lambert et al., 1989; Charlet
et al., 1996), but the evolutionary relationships
between vertebrate, plant, and invertebrate defensins
remain uncertain.
Alternative names
Initial naming of several defensins put emphasis on
their tissue of origin, e.g. human neutrophil peptides
1�(HNP-1 to HNP-3) (Ganz et al., 1985) also
known as human defensins 1� macrophage cationic
peptides 1 and 2 (Lehrer et al., 1983) also known as
rabbit defensins 1 and 2, or skin antimicrobial peptide
(Harder et al., 1997), now known as human defensin 2 (HBD-2). Other designations emphasized
alternative activity, e.g. corticostatins, so named
because of the inhibitory effect of some defensins on
the production of cortisol by adrenal cells (Zhu et al.,
1358 Tomas Ganz
Vertebrate defensins are 29� amino acid sheetrich cationic and amphipathic peptides with a
conserved three disulfide-linked structure. There are
two subfamilies, -defensins (Selsted and Harwig,
1989; Hill et al., 1991), whose six cysteines are linked
1� 2� 3� and -defensins (Tang and Selsted,
1993; Zimmermann et al., 1995), linked 1� 2� 3�
Since cysteines 5 and 6 are always adjacent to one
another the two subfamilies are structurally very
similar (Figure 1 and Figure 2).
Main activities and
pathophysiological roles
Defensins have a broad-spectrum antimicrobial activity in vitro (Ganz and Lehrer, 1995) against grampositive and gram-negative bacteria, yeasts, and
fungi, and enveloped viruses. Their common mechanism of action is membrane permeabilization followed
by interactions with additional as yet undefined
intracellular targets. Their differential activity against
microbes may be dependent on differences in membrane composition between microbial membranes
(rich in anionic phospholipids) and host membranes
(rich in cholesterol and neutral phospholipids). Other
reported activities include in vitro inhibition of
cortisol production by blockade of ACTH receptors
(Solomon et al., 1991), chemoattraction for mononuclear cells, including T lymphocytes (Chertov et al.,
1996), observed in vitro, in immunocompetent mice
and in chimeric huPBL-SCID mice, and stimulation
of phagocyte accumulation at sites of infection and
phagocytic antimicrobial activity in the mouse model
(Welling et al., 1998). Some defensins are opsonic
(Fleischmann et al., 1985) or increase adherence of
bacteria to epithelial surfaces (Gorter et al., 1998).
Accession numbers
Table 1 contains a list of accession numbers for
known human and animal defensin genes and
Figure 1 The three-dimensional molecular structure of human neutrophil defensin HNP-3 (Hill et al., 1991). (Full
colour figure may be viewed online.)
Defensins 1359
Figure 2 The three-dimensional molecular structure of bovine neutrophil
-defensin-12 (Zimmermann et al., 1995). (Full colour figure may be viewed
Chromosome location
Human defensin genes are located in a single cluster
on chromosome 8p23 spanning about 400 kb (Liu
et al., 1997, 1998). The mouse (Ouellette et al., 1989b)
defensin (cryptdin) gene cluster is also located on
chromosome 8 in a location syntenic to that of the
human defensin cluster, as is the bovine defensin cluster
(Gallagher et al., 1995) on bovine chromosome 27.
and the promoter regions of these defensins contain
NFB-binding sites (Russell et al., 1996). The synthesis
of human epithelial defensin HBD-2 (but not HBD-1)
is also inducible by bacteria, TNF and IL-1 (Harder
et al., 1997; Singh et al., 1998) and the promoter of
HBD-2, but not HBD-1, contains multiple NFB sites
(Liu et al., 1998). Consistent with their myeloid-specific
expression, the promoter regions of human neutrophil
defensins contain the binding site for the myeloid factor
PU.1 (Ma et al., 1998).
Regulatory sites and corresponding
transcription factors
Cells and tissues that express
the gene
The production of bovine epithelial defensins TAP
and LAP is inducible by lipopolysaccharide and TNF,
The known defensins follow three patterns of expression: (1) granulocyte-specific, with synthesis occurring
1360 Tomas Ganz
Table 1 Defensin genes, mRNAs, and their accession numbers
Human neutrophil
defensins, HNP-1 to HNP-3
L12690, U10268
M21130, M21131, M23281,
M26602, X52053, X13621
Human neutrophil
defensin, HNP-4
Human Paneth cell
defensin, HD-5
Human Paneth cell
defensin, HD-6
Human -defensin-1
Z50788, X92744, U73945
Human -defensin-2
Rhesus (Macaca mulatta)
Rabbit neutrophil and
macrophage defensins
M28072, M28073,
M28883, M28884, M64600,
M64601, M64602, L10841, L10842
Mouse cryptdins
S73391, U03028, U03030, U03032,
U03033, U03034, U03035, U03036,
U03037, U03064, U03065, U03066,
U03067, U73623, U73624, X15617
Mouse -defensins
U03062, U03063,
U12560, U12561,
U12563, U12564,
Rat neutrophil defensins
U16683, U16684, U16685, U16686
Rat -defensins
AF093536, AF068860, AF068861
Bovine neutrophil -defensins
Bovine enteric -defensins
Sheep -defensins
U75250, U75251
Porcine -defensins
Chicken and turkey -defensins
AF033335, AF033336, AF033337,
in promyelocytic bone marrow precursors (neutrophil
defensins of mammalian and avian species) (Daher
et al., 1988; Ganz et al., 1989; Nagaoka et al., 1993;
Yount et al., 1995; Brockus et al., 1998); (2) Paneth cellspecific (human defensins 5 and 6, mouse cryptdins)
(Ouellette et al., 1989a; Ouellette and Lualdi, 1990;
Jones and Bevins, 1992, 1993; Ouellette and Selsted,
1996); (3) epithelial cells with predominant expression
in the tongue (porcine -defensin 1, bovine lingual
antimicrobial peptide) (Schonwetter et al., 1995; Zhang
et al., 1998), trachea (bovine tracheal antimicrobial
peptide) (Diamond et al., 1993), small intestine and
colon (bovine enteric -defensin) (Tarver et al., 1998),
kidney (human -defensin 1, rabbit defensins RK-1
and RK-2) (Bateman et al., 1996; Valore et al., 1998;
Wu et al., 1998) and skin (human -defensin 2) (Harder
et al., 1997).
Accession numbers
Accession numbers of defensin peptide sequences
in the Entrez (NCBI/NLM) database are listed in
Table 2.
The canonical sequence of -defensins is xxCxCxxxxx
CxxxxxxxGxCxxxxxxxxxCCxx, where x represents
any amino acid and cysteines 1� 2� and 3�are linked. For -defensins the canonical sequence
is CxxxxxxCxxxxCPxxxxxxxxCxxxxx(x)CCxx, where
cysteines 1� 2� and 3�are linked. In general,
Defensins 1361
Table 2 Defensin peptides and their accession numbersa
Species and name
Accession numbers
Human neutrophil peptides 1� 4
Granulocytes, bone marrow
B40499, P11479, P12838, 30501, S65412,
S65413, S65414, A47365, A40499, 292365,
29735, 665927, 181535, 181529, 181527,
292363, 553252
Human defensins 5, 6
Paneth cells
A44454, S27016, Q01523, Q01524, 1200182,
181547, 181533
Human -defensins 1�
949876, 1755148, S66282, Q09573, 1293651,
1617088, O15263, 2239128, 3818537, 3510600
Rhesus -defensin 1
O18794, 2317750
Rabbit macrophage cationic
peptides, neutrophil peptides
Macrophages (1 and 2),
(1, 2, 3, 3A, 4, 5, 6)
WTRBM1, WTRBM2, P01376, P01377,
S32553, JC1462, P07466, P07467, P07468,
P07469, P80223, 415517, 415518, 1912193A,
1912193B, 1904312A, 1904312B, 1904312C,
165561, 165559, 165478, 165476, 165474,
165472, 164999, 164997, 164995, 164993
Rabbit kidney peptides
Mouse cryptdins
Paneth cells
437220, 437224, 437228, 437232, 437236,
437242, 437244, 437246, 437248, 437250,
437252, 437254, 437256, 437258, 437260,
437262, 437264, 437266, 437268, 437270,
497034, 497032, 531839, 531841, 531843,
531845, I48226, I49102, I49103, I49104,
B44800, P11477, P28309, P28310, P28311,
P28312, P50704, P50705, P50706, P50707,
P50708, P50709, P50711, P50712, P50713,
P50714, Q64016, 1245979, 1245980, 1245981,
1657995, 1657997, 1813205A, 50578, 192791
Mouse -defensins 1, 2
2197075, P56386
Rat neutrophil peptides 1�
Granulocytes, bone marrow
A61014, B61014, D61014, E61014, I46703,
I46704, I46705, I46706, S14314, S36843,
S36844, Q62713, Q62714, Q62715, Q62716,
1041805, 1041807, 1041809, 1041811
Rat -defensins 1, 2
3366932, 3668412, 3366934
Guinea pig neutrophil peptides
Granulocytes, bone marrow
P11478, P49112
Hamster neutrophil peptides 1�
Granulocytes, bone marrow
P81465, P81466, P81467, P81468, 1911754,
1911755, 1911756, 1911757
Bovine neutrophil -defensins
Granulocytes, bone marrow
2367667, 2360981, 2360983, 2360985,
2145044, 225845, 298766, 298767, 298768,
298769, 298770, 298771, 298772, 298773,
298774, 298775, 298776, 298777, 298778,
A45495, C45495, D45495, E45495, F45495,
G45495, I45495, A47753, B47753, C47753,
D47753, O02775, P46159, P46160, P46161,
P46162, P46163, P46164, P46165, P46166,
P46167, P46168, P46169, P46170, P25068,
1BNB, Q28880
Tracheal antimicrobial peptide,
lingual antimicrobial peptide,
enteric -defensin
Epithelia of the trachea,
tongue and the digestive tract
P25068, Q28880, O02775, 2367667, 2145444
Sheep -defensins 1, 2
O19038, O19039, 2231305, 2231307
Pig -defensin 1
2978564, O62697
1362 Tomas Ganz
Table 2 (Continued )
Species and name
Acession numbers
Gallinacins, chicken
heterophil peptides
Granulocytes, bone marrow
P46156, P46157, P46158, 3617829, 3617831
Turkey heterophil peptides 1, 2
Granulocytes, bone marrow
3617833, 3617835
Note that the Entrez database (National Library of Medicine) contains many partially and completely redundant entries.
We made no effort to sort through the redundancies and did not include fragmentary or patent sequences.
defensins are rich in cationic amino acids, lysine, and
Description of protein
Defensins are sheet-rich amphipathic peptides with
a conserved disulfide-stabilized structure containing
29� amino acids.
Discussion of crystal structure
In crystals and in solutions human neutrophil
defensins HNP-1 to HNP-3 form homodimers (Hill
et al., 1991) but other - and -defensins are
monomeric in solution (Bach et al., 1987; Pardi
et al., 1988; Levy et al., 1989; Kominos et al., 1990;
Pardi et al., 1992; Zhang et al., 1992; Skalicky et al.,
1994; Zimmermann et al., 1995). The molecular
structures of representative - and -defensins are
shown in Figure 1 and Figure 2 (PDB format). Studies
in model membranes suggest that defensins form
multimeric pores. A model of the pore consistent with
the available data has been proposed (Wimley et al.,
1994; White et al., 1995). The pore is formed by a ring
of six defensin dimers whose arginines associate with
phosphate head groups or point into the channel,
while the hydrophobic side chains are immersed in the
hydrophobic interior of the membrane.
Important homologies
There is significant similarity of -defensins to snake
(crotalid) myotoxins, indicating a possible common
evolutionary origin. Defensin folds exhibit similarity
to insect defensins, scorpion toxins, and sea anemone
toxins (Mas et al., 1998).
Posttranslational modifications
Defensins are synthesized as larger precursors, typically 64�0 amino acids long, with a 19 amino acid
signal sequence and a variable, typically anionic
propeptide segment (Michaelson et al., 1992). Posttranslation modifications include the proteolytic
removal of the signal sequence followed by further
proteolytic cleavages in the Golgi and the nascent
neutrophil granules to remove segments of the Nterminal propiece (Valore and Ganz, 1992). Compared
to -defensin propieces, which consist of around 40�
45 amino acids, -defensin propieces are generally
very short. The processing of epithelial -defensins
generates multiple forms differing in N-terminal truncation, a mechanism which could serve to increase the
diversity of antimicrobial peptides (Valore et al., 1998).
Cellular sources that produce
Defensin peptides are generally expressed in the same
cells that express the genes, i.e. promyelocytic bone
marrow precursors, Paneth cells, and epithelial cells.
The mature granulocytes of many animal species contain abundant neutrophil defensins accumulated during
development of precursor cells in the bone marrow.
However, they no longer contain defensin mRNA
and do not actively synthesize defensin, only storing
previously synthesized defensins in their granules.
In vitro findings
Most defensins manifest broad-spectrum antimicrobial activity at 1� mM concentrations, including
activity against gram-positive and gram-negative
bacteria, yeast, and fungi (Patterson Delafield et al.,
1980; Lehrer et al., 1983, 1985a, 1986, 1988, 1989;
Selsted et al., 1984, 1985b; Ganz et al., 1985; Segal
Defensins 1363
et al., 1985; Levitz et al., 1986; Miyasaki et al., 1990;
Ogata et al., 1992; Couto et al., 1994), Giardia (Aley
et al., 1994), and enveloped viruses (Lehrer et al.,
1985b; Daher et al., 1986). Individual molecular
species differ in their antimicrobial spectra but systematic understanding of these differences has not yet
been achieved. At higher concentrations (15� mM)
cytotoxic activity against cells grown in vitro has been
observed (Lichtenstein et al., 1986, 1988a, 1988b;
Okrent et al., 1990; Lichtenstein, 1991). Chemotactic
activity for mononuclear cells (Territo et al., 1989),
later identified as T lymphocytes (Chertov et al.,
1996), has been shown at nanomolar concentrations.
At 100 nM concentrations, some defensins bind to
ACTH receptors on cortisol-producing adrenal cells
and inhibit ACTH-mediated activation (corticostatic
activity) (Tominaga et al., 1990; Zhu and Solomon,
1992). Other reported activities include opsonization
(Fleischmann et al., 1985; Ichinose et al., 1996) by
some defensins and inhibition of phagocytosis by
others (Ichinose and Sawada, 1995). Defensins bind
to complement components (Panyutich et al., 1994;
van den Berg et al., 1998) and inhibit the activation of
the classical complement pathway.
Mitogenic effects on fibroblasts and other cells
have been reported and these could have a role in
wound healing (Murphy et al., 1993). Most recently,
human neutrophil defensins have been found to
inhibit fibrinolysis (Higazi et al., 1995, 1996) and
promote the uptake of lipoprotein (a) by endothelial
cells (Barnathan et al., 1997; Higazi et al., 1997),
activities that could accelerate the development of
atherosclerosis and its complications.
Regulatory molecules: Inhibitors
and enhancers
The antibacterial and antifungal activity of defensins
is competitively inhibited by increasing concentrations of salt, divalent cations, and serum but the
magnitude of inhibition depends on the target (Lehrer
et al., 1985a, 1988, 1989; Ganz and Lehrer, 1995;
Goldman et al., 1997; Porter et al., 1997; Bals et al.,
1998a, 1998b; Singh et al., 1998; Valore et al., 1998).
Antiviral effects of defensins are not affected by salt
concentrations (Lehrer et al., 1985b; Daher et al., 1986).
Defensins bind avidly to serum proteins, including
2 -macroglobulin, components of complement, and
1 -proteinase inhibitor (1 -antitrypsin) (Panyutich
and Ganz, 1991; Panyutich et al., 1994, 1995; van den
Berg et al., 1998). The ionic and protein composition
of plasma may restrict defensin antimicrobial activity
predominantly to sequestered environments where the
salt and serum concentrations are low (e.g. epithelial
surfaces) or where defensin concentrations are so high
that the inhibitors are overcome (e.g. the phagosomes
of neutrophils). At lower concentrations of defensins
in nonpermissive environments the regulatory effects
of defensins may predominate.
Bioassays used
None of the bioassays are sufficiently specific for
defensins to be useful in their quantification or
Normal physiological roles
The evidence for the normal physiologic role of
defensins as antimicrobial effectors is indirect.
Neutrophil defensins reach high, almost certainly
microbicidal concentrations in the phagolysosome
(Ganz, 1987; Joiner et al., 1989), the site of phagocytic
killing of microorganisms. The local concentrations
of epithelial defensins have not yet been reported.
Subcutaneous administration of human neutrophil
defensins (Chertov et al., 1996) to BALB/c mice
resulted in a moderate neutrophil and mononuclear
cell infiltrate at the site of injection by 4 hours, which
was further increased by 24 hours. Additionally,
subcutaneous injection of defensins into chimeric
huPBL-SCID mice caused significant infiltration by
human CD3+ cells within 4 hours. Potentiation of
microbicidal activity of neutrophils in mice by very
small intravenous doses of human defensin HNP-1
was recently reported (Welling et al., 1998) and may
be mediated by increased accumulation of neutrophils
at the sites of infection in mice primed by intravenous
injections of HNP-1.
Species differences
Although defensins have been detected in many
mammalian and avian species, the tissue distribution
is variable. Thus mice lack neutrophil defensins
altogether (Eisenhauer and Lehrer, 1992), while rats
have several neutrophil defensins (Eisenhauer et al.,
1989, 1990; Yount et al., 1995). Mice express more
than 20 defensin genes in Paneth cells of the small
intestine (Huttner et al., 1994; Ouellette and Selsted,
1996) but humans have only two (Mallow et al.,
1996). Systematic understanding of the evolution and
1364 Tomas Ganz
patterns of expression in different animal species has
not yet been achieved.
Normal levels and effects
Human neutrophils contain 4�mg of HNP-1 to
HNP-3 per million cells. Plasma from healthy donors
contains less than 100 ng/mL of HNP-1 to HNP-3 but
these concentrations rise many-fold during infections,
reaching over 100 mg/mL in some severely septicemic
patients (Panyutich et al., 1993; Shiomi et al., 1993;
Ihi et al., 1997).
Role in experiments of nature and
disease states
Patients with a disorder of neutrophil maturation,
specific granule deficiency, have about 10% of the
normal defensin content in their neutrophils (Ganz
et al., 1988), and suffer from frequent and severe
infections. Because multiple neutrophil proteins are
affected in this disorder, the clinical picture cannot be
attributed solely to defensin deficiency.
Defensins accumulate in atherosclerotic plaques
and have been implicated in the pathogenesis of
atherosclerosis and its thrombotic complications
(Higazi et al., 1995, 1996, 1997; Barnathan et al.,
1997). The colonization of airways by bacteria in
cystic fibrosis has been attributed to the inactivation
of epithelial defensins by increased salt concentrations
in respiratory secretions (Smith et al., 1996; Goldman
et al., 1997; Bals et al., 1998b).
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Defensins 1365
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The following manufacturers sell defensin peptides or
antibodies. The licensing status of the products has
not been ascertained.
Human neutrophil defensin HNP-1
Phoenix Pharmaceuticals, Inc., Mountain View, CA, USA
Tel: 650 988 9220, Fax: 650 988 9221,
Human neutrophil defensins HNP-1 and HNP-2
Sigma Chemical Company/Sigma-Aldrich Corp,
St Louis, MO, USA
Tel: 314 771 5765, Fax: 314 286 8304
Human neutrophil defensins HNP-1 and HNP-2
American Peptide Company, Inc., 777 East Evelyn Ave.,
Sunnyvale, CA 94086, USA
Tel: 408 733 7604 or 1 800 926 8272, Fax: 408 733 7603 or
1 888 670 0070, E-mail:
Monoclonal antibody to human neutrophil
defensins HNP-1 to HNP-3
Accurate Chemical & Scientific Corp., Westbury, NY, USA
Tel: 516 333 2221, Toll Free: 800 645 6264, Fax: 516 997 4948
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