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

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Defensins
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: ganz@ucla.edu
DOI: 10.1006/rwcy.2000.12006.
SUMMARY
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.
BACKGROUND
Discovery
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.,
1988).
1358 Tomas Ganz
Structure
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).
GENE AND GENE REGULATION
Accession numbers
Table 1 contains a list of accession numbers for
known human and animal defensin genes and
mRNAs.
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
online.)
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
Product
Gene(s)
mRNA(s)
HUGO
Human neutrophil
defensins, HNP-1 to HNP-3
L12690, U10268
M21130, M21131, M23281,
M26602, X52053, X13621
HDEFA1
Human neutrophil
defensin, HNP-4
U18745
X65977
HDEFA4
Human Paneth cell
defensin, HD-5
M97925
Human Paneth cell
defensin, HD-6
U33317
M98331
Human -defensin-1
SEG_HSBDONE
Z50788, X92744, U73945
HDEFB1
Human -defensin-2
AF071216
Z71389
HDEFB2
HDEFA5
Rhesus (Macaca mulatta)
-defensin
AF014016
Rabbit neutrophil and
macrophage defensins
M28072, M28073,
M64599
M28883, M28884, M64600,
M64601, M64602, L10841, L10842
Mouse cryptdins
U03061,
U12559,
U12562,
U12565,
S73391, U03028, U03030, U03032,
U03033, U03034, U03035, U03036,
U03037, U03064, U03065, U03066,
U03067, U73623, U73624, X15617
Mouse -defensins
SEG_MMDEFEN0
U03062, U03063,
U12560, U12561,
U12563, U12564,
U12566
Rat neutrophil defensins
U16683, U16684, U16685, U16686
Rat -defensins
AF093536, AF068860, AF068861
Bovine neutrophil -defensins
HDEFA6
AF008307
Bovine enteric -defensins
AF016539
Sheep -defensins
U75250, U75251
AF000362
Porcine -defensins
AF031666
Chicken and turkey -defensins
AF033335, AF033336, AF033337,
AF033338
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).
PROTEIN
Accession numbers
Accession numbers of defensin peptide sequences
in the Entrez (NCBI/NLM) database are listed in
Table 2.
Sequence
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
Tissue
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�
Epithelia
949876, 1755148, S66282, Q09573, 1293651,
1617088, O15263, 2239128, 3818537, 3510600
Rhesus -defensin 1
Epithelia
O18794, 2317750
Rabbit macrophage cationic
peptides, neutrophil peptides
Macrophages (1 and 2),
granulocytes
(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
Kidney
1839443
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
Epithelia
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
Epithelia
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
Epithelia
O19038, O19039, 2231305, 2231307
Pig -defensin 1
Tongue
2978564, O62697
1362 Tomas Ganz
Table 2 (Continued )
Species and name
Tissue
Acession numbers
Gallinacins, chicken
heterophil peptides
Granulocytes, bone marrow
P46156, P46157, P46158, 3617829, 3617831
Turkey heterophil peptides 1, 2
Granulocytes, bone marrow
3617833, 3617835
a
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
arginine.
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 AND
TISSUE EXPRESSION
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 ACTIVITIES
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
identification.
IN VIVO BIOLOGICAL
ACTIVITIES OF LIGANDS IN
ANIMAL MODELS
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.
PATHOPHYSIOLOGICAL ROLES
IN NORMAL HUMANS AND
DISEASE STATES AND
DIAGNOSTIC UTILITY
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).
References
Aley, S. B., Zimmerman, M., Hetsko, M., Selsted, M. E., and
Gillin, F. D. (1994). Killing of Giardia lamblia by cryptdins
and cationic neutrophil peptides. Infect. Immun. 62, 5397�03.
Bach, A.C. II, Selsted, M. E., and Pardi, A. (1987). Two-dimensional NMR studies of the antimicrobial peptide NP-5.
Biochemistry 26, 4389�97.
Bals, R., Goldman, M. J., and Wilson, J. M. (1998a). Mouse betadefensin 1 is a salt-sensitive antimicrobial peptide present in
epithelia of the lung and urogenital tract. Infect. Immun. 66,
1225�32.
Bals, R., Wang, X., Wu, Z., Freeman, T., Bafna, V., Zasloff, M.,
and Wilson, J. M. (1998b). Human beta-defensin 2 is a saltsensitive peptide antibiotic expressed in human lung. J. Clin.
Invest. 102, 874�0.
Barnathan, E. S., Raghunath, P. N., Tomaszewski, J. E., Ganz, T.,
Cines, D. B., and Higazi, A. A.-R. (1997). Immunohistochemical localization of defensin in human coronary vessels.
Am. J. Pathol. 150, 1009�20.
Bateman, A., MacLeod, R. J., Lembessis, P., Hu, J., Esch, F., and
Solomon, S. (1996). The isolation and characterization of a
novel corticostatin/defensin-like peptide from the kidney.
J. Biol. Chem. 271, 10654�659.
Bensch, K. W., Raida, M., Magert, H. J., Schulz-Knappe, P., and
Forssmann, W. G. (1995). hBD-1: a novel beta-defensin from
human plasma. FEBS Lett. 368, 331�5.
Brockus, C. W., Jackwood, M. W., and Harmon, B. G. (1998).
Characterization of beta-defensin prepropeptide mRNA from
chicken and turkey bone marrow. Anim. Genet. 29, 283�9.
Broekaert, W. F., Terras, F. R., Cammue, B. P., and Osborn, R. W.
(1995). Plant defensins: novel antimicrobial peptides as components of the host defense system. Plant Physiol. 108, 1353�58.
Charlet, M., Chernysh, S., Philippe, H., Hetru, C., Hoffmann, J. A.,
and Bulet, P. (1996). Innate immunity. Isolation of several
cysteine-rich antimicrobial peptides from the blood of a mollusc, Mytilus edulis. J. Biol. Chem. 271, 21808�813.
Chertov, O., Michiel, D. F., Xu, L., Wang, J. M., Tani, K.,
Murphy, W. J., Longo, D. L., Taub, D. D., and
Oppenheim, J. J. (1996). Identification of defensin-1, defensin2, and CAP37/azurocidin as T-cell chemoattractant proteins
released from interleukin-8-stimulated neutrophils. J. Biol.
Chem. 271, 2935�40.
Couto, M. A., Liu, L., Lehrer, R. I., and Ganz, T. (1994).
Inhibition of intracellular Histoplasma capsulatum replication
by murine macrophages that produce human defensin. Infect.
Immun. 62, 2375�78.
Daher, K. A., Selsted, M. E., and Lehrer, R. I. (1986). Direct
inactivation of viruses by human granulocyte defensins.
J. Virol. 60, 1068�74.
Daher, K. A., Lehrer, R. I., Ganz, T., and Kronenberg, M. (1988).
Isolation and characterization of human defensin cDNA clones.
Proc. Natl Acad. Sci. USA 85, 7327�31.
Diamond, G., Zasloff, M., Eck, H., Brasseur, M., Maloy, W. L.,
and Bevins, C. L. (1991). Tracheal antimicrobial peptide, a
cysteine-rich peptide from mammalian tracheal mucosa: peptide
isolation and cloning of a cDNA. Proc. Natl Acad. Sci. USA 88,
3952�56.
Diamond, G., Jones, D. E., and Bevins, C. L. (1993). Airway epithelial cells are the site of expression of a mammalian antimicrobial
peptide gene. Proc. Natl Acad. Sci. USA 90, 4596�00.
Eisenhauer, P. B., and Lehrer, R. I. (1992). Mouse neutrophils
lack defensins. Infect. Immun. 60, 3446�47.
Eisenhauer, P. B., Harwig, S. S., Szklarek, D., Ganz, T.,
Selsted, M. E., and Lehrer, R. I. (1989). Purification and antimicrobial properties of three defensins from rat neutrophils.
Infect. Immun. 57, 2021�27.
Eisenhauer, P., Harwig, S. S., Szklarek, D., Ganz, T., and
Lehrer, R. I. (1990). Polymorphic expression of defensins in
neutrophils from outbred rats. Infect. Immun. 58, 3899�02.
Evans, E. W., Beach, G. G., Wunderlich, J., and Harmon, B. G.
(1994). Isolation of antimicrobial peptides from avian heterophils. J. Leukoc. Biol. 56, 661�5.
Fleischmann, J., Selsted, M. E., and Lehrer, R. I. (1985). Opsonic
activity of MCP-1 and MCP-2, cationic peptides from rabbit
alveolar macrophages. Diagn. Microbiol. Infect. Dis. 3, 233�2.
Gallagher, D. S. J., Ryan, A. M., Diamond, G., Bevins, C. L., and
Womack, J. E. (1995). Somatic cell mapping of beta-defensin
genes to cattle syntenic group U25 and fluorescence in situ localization to chromosome 27. Mamm. Genome 6, 554�6.
Ganz, T. (1987). Extracellular release of antimicrobial defensins
by human polymorphonuclear leukocytes. Infect. Immun. 55,
568�1.
Defensins 1365
Ganz, T., and Lehrer, R. I. (1995). Defensins. Pharmacol. Ther.
66, 191�5.
Ganz, T., Selsted, M. E., Szklarek, D., Harwig, S. S., Daher, K.,
Bainton, D. F., and Lehrer, R. I. (1985). Defensins. Natural
peptide antibiotics of human neutrophils. J. Clin. Invest. 76,
1427�35.
Ganz, T., Metcalf, J. A., Gallin, J. I., Boxer, L. A., and Lehrer, R. I.
(1988). Microbicidal/cytotoxic proteins of neutrophils are deficient in two disorders: Chediak-Higashi syndrome and `specific'
granule deficiency. J. Clin. Invest. 82, 552�6.
Ganz, T., Rayner, J. R., Valore, E. V., Tumolo, A., Talmadge, K.,
and Fuller, F. (1989). The structure of the rabbit macrophage
defensin genes and their organ-specific expression. J. Immunol.
143, 1358�65.
Goldman, M., Anderson, G., Stolzenberg, E. D., Kari, U. P.,
Zasloff, M., and Wilson, J. M. (1997). Human beta-defensin-1
is a salt-sensitive antibiotic in lung that is inactivated in cystic
fibrosis. Cell 88, 553�0.
Gorter, A. D., Eijk, P. P., Van Wetering, S., Hiemstra, P. S.,
Dankert, J., and van Alphen, L. (1998). Stimulation of the
adherence of Haemophilus influenzae to human lung epithelial
cells by antimicrobial neutrophil defensins. J. Infect. Dis. 178,
1067�74.
Harder, J., Bartels, J., Christophers, E., and Schroeder, J.-M. (1997).
A peptide antibiotic from human skin. Nature 387, 861�2.
Harwig, S. S., Swiderek, K. M., Kokryakov, V. N., Tan, L.,
Lee, T. D., Panyutich, E. A., Aleshina, G. M., Shamova, O. V.,
and Lehrer, R. I. (1994). Gallinacins: cysteine-rich antimicrobial
peptides of chicken leukocytes. FEBS Lett. 342, 281�5.
Higazi, A. A., Barghouti, I. I., and Abu-Much, R. (1995).
Identification of an inhibitor of tissue-type plasminogen activator-mediated fibrinolysis in human neutrophils. A role for
defensin. J. Biol. Chem. 270, 9472�77.
Higazi, A. A. R., Ganz, T., Kariko, K., and Cines, D. B. (1996).
Defensin modulates tissue-type plasminogen activator and plasminogen binding to fibrin and endothelial cells. J. Biol. Chem.
271, 17650�655.
Higazi, A. A., Lavi, E., Bdeir, K., Ulrich, A. M., Jamieson, D. G.,
Rader, D. J., Usher, D. C., Kane, W., Ganz, T., and Cines, D. B.
(1997). Defensin stimulates the binding of lipoprotein (a) to
human vascular endothelial and smooth muscle cells. Blood
89, 4290�98.
Hill, C. P., Yee, J., Selsted, M. E., and Eisenberg, D. (1991).
Crystal structure of defensin HNP-3, an amphiphilic dimer:
mechanisms of membrane permeabilization. Science 251,
1481�85.
Huttner, K. M., Selsted, M. E., and Ouellette, A. J. (1994).
Structure and diversity of the murine cryptdin gene family.
Genomics 19, 448�3.
Huttner, K. M., Kozak, C. A., and Bevins, C. L. (1997). The
mouse genome encodes a single homolog of the antimicrobial
peptide human beta-defensin 1. FEBS Lett. 413, 45�.
Huttner, K. M., Lambeth, M. R., Burkin, H. R., Burkin, D. J.,
and Broad, T. E. (1998). Localization and genomic organization
of sheep antimicrobial peptide genes. Gene 206, 85�.
Ichinose, M., and Sawada, M. (1995). A flow cytometric
assay reveals a suppression of phagocytosis by rabbit defensin
NP-3A in mouse peritoneal macrophages. Microbiol. Immunol.
39, 365�7.
Ichinose, M., Asai, M., Imai, K., and Sawada, M. (1996).
Enhancement of phagocytosis by corticostatin I (CSI) in cultured mouse peritoneal macrophages. Immunopharmacology 35,
103�9.
Ihi, T., Nakazato, M., Mukae, H., and Matsukura, S. (1997).
Elevated concentrations of human neutrophil peptides in
plasma, blood, and body fluids from patients with infections
[see comments]. Clin. Infect. Dis. 25, 1134�40.
Joiner, K. A., Ganz, T., Albert, J., and Rotrosen, D. (1989). The
opsonizing ligand on Salmonella typhimurium influences incorporation of specific, but not azurophil, granule constituents into
neutrophil phagosomes. J. Cell Biol. 109, 2771�82.
Jones, D. E., and Bevins, C. L. (1992). Paneth cells of the human
small intestine express an antimicrobial peptide gene. J. Biol.
Chem. 267, 23216�225.
Jones, D. E., and Bevins, C. L. (1993). Defensin-6 mRNA in
human Paneth cells: implications for antimicrobial peptides in
host defense of the human bowel. FEBS Lett. 315, 187�2.
Kominos, D., Bassolino, D. A., Levy, R. M., and Pardi, A. (1990).
Analysis of side-chain conformational distributions in neutrophil
peptide-5 NMR structures. Biopolymers 29, 1807�22.
Lambert, J., Keppi, E., Dimarcq, J. L., Wicker, C.,
Reichhart, J. M., Dunbar, B., Lepage, P., Van Dorsselaer, A.,
Hoffmann, J., Fothergill, J., and Hoffmann, D. (1989). Insect
immunity: isolation from immune blood of the dipteran
Phormia terranovae of two insect antibacterial peptides with
sequence homology to rabbit lung macrophage bactericidal peptides. Proc. Natl Acad. Sci. USA 86, 262�6.
Lehrer, R. I., Selsted, M. E., Szklarek, D., and Fleischmann, J.
(1983). Antibacterial activity of microbicidal cationic proteins 1
and 2, natural peptide antibiotics of rabbit lung macrophages.
Infect. Immun. 42, 10�.
Lehrer, R. I., Szklarek, D., Ganz, T., and Selsted, M. E. (1985a).
Correlation of binding of rabbit granulocyte peptides to
Candida albicans with candidacidal activity. Infect. Immun. 49,
207�1.
Lehrer, R. I., Daher, K., Ganz, T., and Selsted, M. E. (1985b).
Direct inactivation of viruses by MCP-1 and MCP-2, natural
peptide antibiotics from rabbit leukocytes. J. Virol. 54, 467�2.
Lehrer, R. I., Szklarek, D., Ganz, T., and Selsted, M. E. (1986).
Synergistic activity of rabbit granulocyte peptides against
Candida albicans. Infect. Immun. 52, 902�4.
Lehrer, R. I., Ganz, T., Szklarek, D., and Selsted, M. E. (1988).
Modulation of the in vitro candidacidal activity of human neutrophil defensins by target cell metabolism and divalent cations.
J. Clin. Invest. 81, 1829�35.
Lehrer, R. I., Barton, A., Daher, K. A., Harwig, S. S., Ganz, T.,
and Selsted, M. E. (1989). Interaction of human defensins with
Escherichia coli. Mechanism of bactericidal activity. J. Clin.
Invest. 84, 553�1.
Levitz, S. M., Selsted, M. E., Ganz, T., Lehrer, R. I., and
Diamond, R. D. (1986). In vitro killing of spores and hyphae
of Aspergillus fumigatus and Rhizopus oryzae by rabbit neutrophil cationic peptides and bronchoalveolar macrophages.
J. Infect. Dis. 154, 483�9.
Levy, R. M., Bassolino, D. A., Kitchen, D. B., and Pardi, A.
(1989). Solution structures of proteins from NMR data and
modeling: alternative folds for neutrophil peptide 5.
Biochemistry 28, 9361�72.
Lichtenstein, A. (1991). Mechanism of mammalian cell lysis
mediated by peptide defensins. Evidence for an initial alteration
of the plasma membrane. J. Clin. Invest. 88, 93�0.
Lichtenstein, A., Ganz, T., Selsted, M. E., and Lehrer, R. I.
(1986). In vitro tumor cell cytolysis mediated by peptide
defensins of human and rabbit granulocytes. Blood 68,
1407�10.
Lichtenstein, A. K., Ganz, T., Selsted, M. E., and Lehrer, R. I.
(1988a). Synergistic cytolysis mediated by hydrogen peroxide combined with peptide defensins. Cell Immunol. 114,
104�6.
Lichtenstein, A. K., Ganz, T., Nguyen, T. M., Selsted, M. E., and
Lehrer, R. I. (1988b). Mechanism of target cytolysis by peptide
defensins. Target cell metabolic activities, possibly involving
endocytosis, are crucial for expression of cytotoxicity.
J. Immunol. 140, 2686�94.
1366 Tomas Ganz
Liu, L., Zhao, C., Heng, H. H. Q., and Ganz, T. (1997). The
human -defensin-1 and -defensins are encoded by adjacent
genes: two peptide families with differing disulfide topology
share a common ancestry. Genomics 43, 316�0.
Liu, L., Wang, L., Jia, H. P., Zhao, C., Heng, H. H. Q.,
Schutte, B. C., McCray, P. B. J., and Ganz, T. (1998). Structure
and mapping of the human -defensin HBD-2 gene and its
expression at sites of inflammation. Gene 222, 237�4.
Ma, Y., Su, Q., and Tempst, P. (1998). Differentiation-stimulated
activity binds an ETS-like, essential regulatory element in the
human promyelocytic defensin-1 promoter. J. Biol. Chem. 273,
8727�40.
Mak, P., Wojcik, K., Thogersen, I. B., and Dubin, A. (1996).
Isolation, antimicrobial activities, and primary structures of
hamster neutrophil defensins. Infect. Immun. 64, 4444�49.
Mallow, E. B., Harris, A., Salzman, N., Russell, J. P.,
DeBerardinis, R. J., Ruchelli, E., and Bevins, C. L. (1996).
Human enteric defensins. Gene structure and developmental
expression. J. Biol. Chem. 271, 4038�45.
Mas, J. M., Aloy, P., Mart, Oliva, B., Blanco-Aparicio, C.,
Molina, M. A., de Llorens, R., Querol, E., and Aviles, F. X.
(1998). Protein similarities beyond disulphide bridge topology.
J. Mol. Biol. 284, 541�8.
Michaelson, D., Rayner, J., Couto, M., and Ganz, T. (1992).
Cationic defensins arise from charge-neutralized propeptides:
a mechanism for avoiding leukocyte autocytotoxicity?
J. Leukoc. Biol. 51, 634�9.
Miyasaki, K. T., Bodeau, A. L., Selsted, M. E., Ganz, T., and
Lehrer, R. I. (1990). Killing of oral, gram-negative, facultative
bacteria by the rabbit defensin, NP-1. Oral Microbiol. Immunol.
5, 315�9.
Murphy, C. J., Foster, B. A., Mannis, M. J., Selsted, M. E., and
Reid, T. W. (1993). Defensins are mitogenic for epithelial cells
and fibroblasts. J. Cell Physiol. 155, 408�3.
Nagaoka, I., Nonoguchi, A., and Yamashita, T. (1993). Cloning
and characterization of the guinea pig neutrophil cationic peptide-1 and -2 genes. DNA Seq. 4, 123�8.
Ogata, K., Linzer, B. A., Zuberi, R. I., Ganz, T., Lehrer, R. I., and
Catanzaro, A. (1992). Activity of defensins from human
neutrophilic granulocytes against Mycobacterium aviumMycobacterium intracellulare. Infect. Immun. 60, 4720�25.
Okrent, D. G., Lichtenstein, A. K., and Ganz, T. (1990). Direct
cytotoxicity of polymorphonuclear leukocyte granule proteins
to human lung-derived cells and endothelial cells. Am. Rev.
Respir. Dis. 141, 179�5.
Ouellette, A. J., and Lualdi, J. C. (1990). A novel mouse gene
family coding for cationic, cysteine-rich peptides. Regulation
in small intestine and cells of myeloid origin. J. Biol. Chem.
265, 9831�37.
Ouellette, A. J., and Selsted, M. E. (1996). Paneth cell defensins:
endogenous peptide components of intestinal host defense.
FASEB J. 10, 1280�89.
Ouellette, A. J., Greco, R. M., James, M., Frederick, D.,
Naftilan, J., and Fallon, J. T. (1989a). Developmental regulation
of cryptdin, a corticostatin/defensin precursor mRNA in mouse
small intestinal crypt epithelium. J. Cell Biol. 108, 1687�95.
Ouellette, A. J., Pravtcheva, D., Ruddle, F. H., and James, M.
(1989b). Localization of the cryptdin locus on mouse chromosome 8. Genomics 5, 233�9.
Panyutich, A., and Ganz, T. (1991). Activated alpha 2-macroglobulin is a principal defensin-binding protein. Am. J. Respir. Cell
Mol. Biol. 5, 101�6.
Panyutich, A. V., Panyutich, E. A., Krapivin, V. A.,
Baturevich, E. A., and Ganz, T. (1993). Plasma defensin concentrations are elevated in patients with septicemia or bacterial
meningitis. J. Lab. Clin. Med. 122, 202�7.
Panyutich, A. V., Szold, O., Poon, P. H., Tseng, Y., and Ganz, T.
(1994). Identification of defensin binding to C1 complement.
FEBS Lett. 356, 169�3.
Panyutich, A. V., Hiemstra, P. S., Van Wetering, S., and Ganz, T.
(1995). Human neutrophil defensin and serpins form complexes
and inactivate each other. Am. J. Respir. Cell Mol. Biol. 12,
351�7.
Pardi, A., Hare, D. R., Selsted, M. E., Morrison, R. D.,
Bassolino, D. A., and Bach, A. C. II (1988). Solution structures
of the rabbit neutrophil defensin NP-5. J. Mol. Biol. 201,
625�6.
Pardi, A., Zhang, X. L., Selsted, M. E., Skalicky, J. J., and
Yip, P. F. (1992). NMR studies of defensin antimicrobial peptides. 2. Three- dimensional structures of rabbit NP-2 and
human HNP-1. Biochemistry 31, 11357�364.
Patterson Delafield, J., Martinez, R. J., and Lehrer, R. I. (1980).
Microbicidal cationic proteins in rabbit alveolar macrophages:
a potential host defense mechanism. Infect. Immun. 30, 180�
192.
Porter, E. M., vanDam, E., Valore, E. V., and Ganz, T. (1997).
Broad-spectrum antimicrobial activity of human intestinal
defensin 5. Infect. Immun. 65, 2396�01.
Russell, J. P., Diamond, G., Tarver, A. P., Scanlin, T. F., and
Bevins, C. L. (1996). Coordinate induction of two antibiotic
genes in tracheal epithelial cells exposed to the inflammatory
mediators lipopolysaccharide and tumor necrosis factor alpha.
Infect. Immun. 64, 1565�68.
Schonwetter, B. S., Stolzenberg, E. D., and Zasloff, M. A. (1995).
Epithelial antibiotics induced at sites of inflammation. Science
267, 1645�48.
Segal, G. P., Lehrer, R. I., and Selsted, M. E. (1985). In vitro effect
of phagocyte cationic peptides on Coccidioides immitis. J. Infect.
Dis. 151, 890�4.
Selsted, M. E., and Harwig, S. S. (1987). Purification, primary
structure, and antimicrobial activities of a guinea pig neutrophil
defensin. Infect. Immun. 55, 2281�86.
Selsted, M. E., and Harwig, S. S. (1989). Determination of the
disulfide array in the human defensin HNP-2. A covalently
cyclized peptide. J. Biol. Chem. 264, 4003�07.
Selsted, M. E., Brown, D. M., DeLange, R. J., and Lehrer, R. I.
(1983). Primary structures of MCP-1 and MCP-2, natural
peptide antibiotics of rabbit lung macrophages. J. Biol. Chem.
258, 14485�489.
Selsted, M. E., Szklarek, D., and Lehrer, R. I. (1984). Purification
and antibacterial activity of antimicrobial peptides of rabbit
granulocytes. Infect. Immun. 45, 150�4.
Selsted, M. E., Harwig, S. S., Ganz, T., Schilling, J. W., and
Lehrer, R. I. (1985a). Primary structures of three human neutrophil defensins. J. Clin. Invest. 76, 1436�39.
Selsted, M. E., Szklarek, D., Ganz, T., and Lehrer, R. I. (1985b).
Activity of rabbit leukocyte peptides against Candida albicans.
Infect. Immun. 49, 202�6.
Selsted, M. E., Brown, D. M., DeLange, R. J., Harwig, S. S., and
Lehrer, R. I. (1985c). Primary structures of six antimicrobial peptides of rabbit peritoneal neutrophils. J. Biol. Chem. 260, 4579�
4584.
Selsted, M. E., Tang, Y. Q., Morris, W. L., McGuire, P. A., Novotny,
M. J., Smith, W., Henschen, A. H., and Cullor, J. S. (1993).
Purification, primary structures, and antibacterial activities of
beta-defensins, a new family of antimicrobial peptides from bovine
neutrophils. J. Biol. Chem. 268, 6641�48.
Shiomi, K., Nakazato, M., Ihi, T., Kangawa, K., Matsuo, H., and
Matsukura, S. (1993). Establishment of radioimmunoassay for
human neutrophil peptides and their increases in plasma and
neutrophil in infection. Biochem. Biophys. Res. Commun. 195,
1336�44.
Defensins 1367
Singh, P. K., Jia, H. P., Wiles, K., Hesselberth, J., Liu, L.,
Conway, B. D., Greenberg, E. P., Valore, E. V., Welsh, M. J.,
Ganz, T., Tack, B. F., and McCray, P. B. J. (1998). Production
of -defensins by human airway epithelia. Proc. Natl Acad. Sci.
USA 95, 14961�966.
Skalicky, J. J., Selsted, M. E., and Pardi, A. (1994). Structure and
dynamics of the neutrophil defensins NP-2, NP-5, and HNP-1:
NMR studies of amide hydrogen exchange kinetics. Proteins 20,
52�.
Smith, J. J., Travis, S. M., Greenberg, E. P., and Welsh, M. J.
(1996). Cystic fibrosis airway epithelia fail to kill bacteria
because of abnormal airway surface fluid. Cell 85, 229�6.
Solomon, S., Hu, J., Zhu, Q., Belcourt, D., Bennett, H. P.,
Bateman, A., and Antakly, T. (1991). Corticostatic peptides.
J. Steroid Biochem. Mol. Biol. 40, 391�8.
Tang, Y. Q., and Selsted, M. E. (1993). Characterization of the
disulfide motif in BNBD-12, an antimicrobial beta-defensin peptide from bovine neutrophils. J. Biol. Chem. 268, 6649�53.
Tarver, A. P., Clark, D. P., Diamond, G., Russell, J. P.,
Erdjument-Bromage, H., Tempst, P., Cohen, K. S., Jones, D. E.,
Sweeney, R. W., Wines, M., Hwang, S., and Bevins, C. L.
(1998). Enteric beta-defensin: molecular cloning and characterization of a gene with inducible intestinal epithelial cell expression associated with Cryptosporidium parvum infection. Infect.
Immun. 66, 1045�56.
Territo, M. C., Ganz, T., Selsted, M. E., and Lehrer, R. (1989).
Monocyte-chemotactic activity of defensins from human neutrophils. J. Clin. Invest. 84, 2017�20.
Tominaga, T., Fukata, J., Naito, Y., Nakai, Y., Funakoshi, S.,
Fujii, N., and Imura, H. (1990). Effects of corticostatin-I on rat
adrenal cells in vitro. J. Endocrinol. 125, 287�2.
Valore, E. V., and Ganz, T. (1992). Posttranslational processing of
defensins in immature human myeloid cells. Blood 79, 1538�44.
Valore, E. V., Park, C. H., Quayle, A. J., Wiles, K. R.,
McCray, P. B., and Ganz, T. (1998). Human beta-defensin-1:
an antimicrobial peptide of urogenital tissues. J. Clin. Invest.
101, 1633�42.
van den Berg, R. H., Faber-Krol, M. C., Van Wetering, S.,
Hiemstra, P. S., and Daha, M. R. (1998). Inhibition of activation of the classical pathway of complement by human neutrophil defensins. Blood 92, 3898�03.
Welling, M. M., Hiemstra, P. S., van den Barselaar, M. T.,
Paulusma-Annema, A., Nibbering, P. H., Pauwels, E. K. J.,
and Calame, W. (1998). Antibacterial activity of human neutrophil defensins in experimental infections in mice is accompanied by increased leukocyte accumulation. J. Clin. Invest. 102,
1583�90.
White, S. H., Wimley, W. C., and Selsted, M. E. (1995). Structure,
function, and membrane integration of defensins. Curr. Opin.
Struct. Biol. 5, 521�7.
Wimley, W. C., Selsted, M. E., and White, S. H. (1994).
Interactions between human defensins and lipid bilayers: evidence for formation of multimeric pores. Protein Sci. 3, 1362�
1373.
Wu, E. R., Daniel, R., and Bateman, A. (1998). RK-2: a novel
rabbit kidney defensin and its implications for renal host
defense. Peptides 19, 793�9.
Yount, N. Y., Wang, M. S. C., Yuan, J., Banaiee, N., Ouellette, A.,
and Selsted, M. E. (1995). Rat neutrophil defensins � precursor
structures and expression during neutrophilic myelopoiesis.
J. Immunol. 155, 4476�84.
Zeya, H. I., and Spitznagel, J. K. (1963). Antibacterial and enzymic basic proteins from leukocyte lysosomes: separation and
identification. Science 142, 1085�87.
Zeya, H. I., and Spitznagel, J. K. (1966). Antimicrobial specificity
of leukocyte lysosomal cationic proteins. Science 154, 1049�
1051.
Zhang, X. L., Selsted, M. E., and Pardi, A. (1992). NMR studies
of defensin antimicrobial peptides. 1. Resonance assignment
and secondary structure determination of rabbit NP-2 and
human HNP-1. Biochemistry 31, 11348�356.
Zhang, G., Wu, H., Shi, J., Ganz, T., Ross, C. R., and Blecha, F.
(1998). Molecular cloning and tissue expression of porcine betadefensin-1. FEBS Lett. 424, 37�.
Zhu, Q., and Solomon, S. (1992). Isolation and mode of action of
rabbit
corticostatic
(antiadrenocorticotropin)
peptides.
Endocrinology 130, 1413�23.
Zhu, Q. Z., Hu, J., Mulay, S., Esch, F., Shimasaki, S., and
Solomon, S. (1988). Isolation and structure of corticostatin peptides from rabbit fetal and adult lung. Proc. Natl Acad. Sci.
USA 85, 592�6.
Zimmermann, G. R., Legault, P., Selsted, M. E., and Pardi, A.
(1995). Solution structure of bovine neutrophil beta-defensin12: the peptide fold of the beta-defensins is identical to that of
the classical defensins. Biochemistry 34, 13663�671.
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