
* Laboratory of Molecular Immunoregulation, Division of Basic Sciences,
Intramural Research Support Program, SAIC Frederick, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland
Correspondence: Dr. Joost J. Oppenheim, LMI, DBS, NCI-FCRDC, Building 560, Room 21-89, Frederick, MD 21702-1201. E-mail: oppenhei{at}mail.ncifcrf.gov
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(TNF-
), dendritic cells lose their
responsiveness to human neutrophil defensins. The chemotactic effect of
human neutrophil defensins on both T and dendritic cells is pertussis
toxin-sensitive, suggesting that a Gi
protein-coupled
receptor is responsible. Human neutrophil defensins are also
chemotactic for immature murine dendritic cells. These data suggest
that, in addition to their antimicrobial role, human neutrophil
defensins also contribute to adaptive immunity by mobilizing T cells
and dendritic cells.
Key Words:
-defensins chemotaxis T lymphocytes
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and ß [2
,
3
]. In humans, six
and two ß defensins have thus
far been characterized [2
, 3
,
5
, 6
]. Human
defensins 5 and 6 are
generated by small intestine Paneth cells [3
], whereas
defensins 1, 2, 3, and 4 are expressed by neutrophils and thus are
termed human neutrophil peptide (HNP) [1
,
7
]. All defensins are considered to contribute to host
defense because they preferentially disrupt the cell membranes of
microorganisms that are rich in negatively charged phospholipids
[1
2
3
, 5
6
7
8
].
In addition to their antimicrobial effects,
defensins have also
been reported to lyse some tumor cells [9
], to
chemoattract monocytes [10
], to block the
adrenocorticotropin receptor [11
], to inhibit NADPH
oxidase activation [12
], to be mitogenic for murine
epithelial cells and fibroblasts [13
], to initiate
[14
] or suppress [15
] the classical
pathway of complement, and to promote the binding of lipoproteins to
vascular matrix [16
]. By analyzing interleukin-8
(IL-8)-induced neutrophil-derived T cell attracting activity, our
laboratory previously established that HNP is chemotactic for human T
cells [17
]. Work from our and others laboratories also
demonstrates that, when administered in vivo together with
antigens, HNP is capable of promoting systemic antigen-specific immune
responses [18, and K. Tani et al., unpublished results].
However, the mechanisms by which HNP enhances adaptive immunity remain
largely unclear.
Quite recently, we documented that human ß defensins induce the migration of both human resting memory T cells and immature dendritic cells (DC) by interacting with CC chemokine receptor 6 and proposed that ß defensins may bridge innate and adaptive immunity of the host [20 ]. Because lymphocytes and DC are participants in adaptive immunity [21 ], we therefore investigated the mechanism by which HNP enhances adaptive immunity by determining: (1) the identity of the subsets of human T cells chemoattracted by HNP, and (2) whether or not HNP was also chemotactic for DCs. The results suggest that HNP selectively targets distinct subsets of T cells and DCs.
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(TNF-
; specific activity
2 x 107
U/mg), granulocyte-macrophage colony-stimulating factor (GM-CSF;
specific activity
107 U/mg), IL-4 (specific
activity
2 x 106 U/mg), and recombinant HNP1
(rHNP1) were purchased from PeproTech (Rocky Hill, NJ).
N-formyl-Met-Leu-Phe (fMLP), synthetic HNP2 (sHNP2), and
chemicals, unless otherwise specified, were purchased from Sigma (St.
Louis, MO). sHNP1 was obtained from Phoenix (Mountain View, CA).
Natural human neutrophil defensins, a mixture of HNP1, 2, and 3
(designated thereafter as HNPm), were isolated from the granules of
polymorphonuclear leukocytes from normal donors as described
[17
]. Amino acid sequence analysis revealed that the
proportion of HNP1/HNP2/HNP3 was 5:3:2 in HNPm. No protein contaminants
were detected in HNPm by amino acid analysis, matrix-assisted laser
desorption ionization, and time-of-flight mass spectrometry.
Cell isolation and purification
Human peripheral blood mononuclear cells (PBMC) were isolated by
Ficoll-Paque density gradient centrifugation. Monocytes were purified
(>95%) from human PBMC with a MACS CD14 monocyte isolation kit
(Miltenyi Biotech, Auburn, CA). Human peripheral blood
CD3+, CD4+, CD8+,
CD4+/CD45RA+, and
CD4+/CD45RO+ T cells were purified from PBMC by
the use of corresponding negative selection columns (R & D Systems,
Minneapolis, MN) following the manufacturers recommendation. The
purity of T cell subset populations was checked by FACScan analysis.
Cell populations with purity less than 95% were discarded. Murine
Sca-1+/Lineage- hematopoietic stem cells
(HSCs) were isolated from the bone marrow of mice (C57BL/6, female, 5-
to 7-week-old) by the use of a Sca-1 MultiSort Kit (Miltenyi Biotech).
Human cord blood CD34+ progenitors (>90%) and
CD3+ T cells (>95%) were purchased from Poietics
(Gaithersburg, MD).
Preparation of DC
Monocyte-derived DCs were generated as described previously
[22
]. In brief, purified monocytes were incubated in the
presence of GM-CSF, IL-4, and transforming growth factor ß1
(TGF-ß1) for 7 days to generate immature DCs (iDCs). Mature DCs
(mDCs) were obtained by incubating iDCs in the same cytokine-containing
medium plus 50 ng/mL of TNF-
for 2 days. CD34+-derived
iDCs and mDCs were prepared from cord blood CD34+
progenitors exactly as described elsewhere [20
]. To
generate murine iDCs, purified murine HSCs were incubated in RPMI 1640
(Biowhittaker, Walkersville, MD) containing 10% FBS, glutamine (2 mM),
HEPES (25 mM), penicillin (100 U/mL), streptomycin (100 µg/mL),
GM-CSF (50 ng/mL), and IL-4 (10 ng/mL) at 37°C in a CO2
(5%) incubator for 5 days. The cultures were fed with the same
cytokine-containing medium every 23 days. Murine mDCs were obtained
by culture of the iDCs in the same cytokine cocktail plus 50 ng/mL of
TNF-
for 2 additional days. All the iDCs used were
CD86-/+, MHC class II++, and unable
to stimulate allogeneic mixed lymphocyte reaction, whereas all mDCs
used were CD86++, MHC class II++++, and highly
capable of mounting marked allogeneic mixed lymphocyte reaction.
Chemotaxis assay
Cell migration was assessed using a 48-well microchemotaxis
chamber. The cells were washed three times and resuspended in
chemotactic medium (CM, RPMI1640 containing 1% BSA). HNP and other
chemotactic factors were diluted with CM. Different concentrations of
chemotactic factors were placed in wells of the lower compartment of
the chamber (Neuro Probe, Cabin John, MD), and cell suspension
(1
5 x 106 cells/mL) was added in wells of the
upper compartment. The lower and upper compartments were separated by a
5-µm polycarbonate filter (Osmonics, Livermore, CA). For T cell
chemotaxis, the filter was coated overnight at 4°C in RPMI 1640
containing 10 µg/mL of fibronectin (Sigma) and air-dried just before
use. After incubation at 37°C for 1.5 (for DCs) or 3 h (for T
cells) in humidified air with 5% CO2, the filters were
removed, stained, and the cells migrated across the filter were counted
with the use of a Bioquant semiautomatic counting system. The results
are presented as either the number of cells per high-power field
(No./HPF) or chemotactic index (CI) defined as the fold increase in the
number of migrating cells in the presence of test factors over the
spontaneous cell migration (in the absence of test factors). The
statistical significance of the increase in cell migration and
difference of cell migration induced by different chemotactic factors
was determined by paired and unpaired t test, respectively.
A CI
2 is statistically significant (P <
0.05).
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![]() View larger version (18K): [in a new window] |
Figure 1. Migration of human peripheral blood CD3+ T cells in
response to HNP. T cell migration was assessed by chemotaxis assay as
described in Materials and Methods. CD3+ T cells were used
at a concentration of 5 x 106 cells/mL. Spontaneous
cell migration (without HNP) was 60 90 cells/HPF. Means ±
SD of triplicate wells are shown. Similar results were
obtained from more than five separate experiments.
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|
View this table: [in a new window] |
Table 1. Chemotaxis of CBT and PBT Cells in Response to HNP
|
![]() View larger version (22K): [in a new window] |
Figure 2. Migration of different subsets of human peripheral blood T cells in
response to HNP. T cell migration was assessed by chemotaxis assay as
described in Materials and Methods. The results are presented as the
means ± SD of triplicate wells. (A) Chemotaxis of
CD4+ and CD8+ T cells by HNPm. CD4+
and CD8+ T cells were used at a concentration of 2 x
106 cells/mL. Spontaneous cell migration (without HNP) was
50 70 cells/HPF. (B) Chemotaxis of naive (CD45RA+) and
memory (CD45RO+) CD4+ T cells by HNPm and
rHNP1. Naive and memory CD4+ T cells were used at a
concentration of 1 x 106 cells/mL. Spontaneous cell
migration (without HNP) was 30 40 cells/HPF. Similar results were
obtained from three separate experiments.
|
, mDCs lost the responsiveness to HNPm (Fig. 3A
,
open circles). Because human DCs can be generated in vitro
not only from monocytes [22
, 25
,
26
], but also from CD34+ progenitors
[20
, 27
], we also examined the effect of
HNP on CD34+ progenitor-derived DCs. Both HNPm and rHNP1
induced the migration of CD34+ progenitor-derived iDCs
(Fig. 3B)
, but not mDCs (data not shown). The effective concentrations
of HNP for inducing human iDC migration (Fig. 3) were similar to those
for inducing T cell migration (Figs. 1 and 2
, Table 1
).
![]() View larger version (25K): [in a new window] |
Figure 3. Induction of human DC migration by HNP. Cell migration was assessed by
chemotaxis assay as described in Materials and Methods. Monocytes and
DCs were used at a concentration of 1 x 106 cells/mL.
Means ± SD of triplicate wells are shown. Spontaneous
cell migration (without HNP) was 40 60 cells/HPF. (A) Migration of
monocytes and monocyte-derived DCs in response to HNPm and sHNP2.
Monocytes and DCs were from the same donor. The error bars were omitted
for clarity. (B) Chemotaxis of CD34+ progenitor-derived
iDCs by HNPm and sHNP1. *P < 0.05. One experiment
representative of three is shown.
|
protein-coupled receptor(s).
PTX pretreatment did not affect spontaneous (in response to CM) cell
migration, ruling out the possibility of nonspecific inhibition of cell
motility. That cell migration induced by RANTES or fMLP was also
inhibited is compatible with the fact that both RANTES and fMLP use
PTX-sensitive G protein-coupled receptors [28
,
29
]. |
View this table: [in a new window] |
Table 2. Inhibition by PTX of HNP-Induced Chemotaxis of Human CD3+ T
and Immature Dendritic Cells
|
-induced maturation,
murine mDCs also lost their responsiveness to HNPm and sHNP1 (Fig. 4 ,
filled symbols).
![]() View larger version (20K): [in a new window] |
Figure 4. Selective chemoattraction of murine iDCs by HNPm and sHNP1. Murine DCs
were used at a concentration of 1 x 106 cells/mL in
the chemotaxis assay. The results are shown as means ±
SD of triplicate wells. Spontaneous cell migration (without
HNP) was 30 40 cells/HPF. One experiment representative of three is
shown.
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DCs are the most potent antigen-presenting cells and are essential for
the initial induction of antigen-specific adaptive immunity
[21
, 35
]. Establishing the capacity of HNP
to chemoattract immature human and murine DCs is of particular
interest. This is in accordance with reports that human
defensins,
when administered together with antigens into mice, promote systemic
antigen-specific immune responses in vivo [18, K. Tani et
al., unpublished results]. Furthermore, this enables us to propose
that, in addition to their microbicidal role [1
,
2
, 7
, 8
], human neutrophil
defensins also play important roles in promoting adaptive immunity
against microorganisms presumably by recruiting immature DCs and T
cells to the sites of microbial infection. Neutrophil defensins may
participate in several in vivo phases of innate and adaptive
immunity against microbial infection: (1) after entry of microorganisms
into the host, phagocytic neutrophils migrate to sites of entry and
phagocytize microbes; (2)
defensins are released by degranulating
neutrophils into the local environment [17
,
36
] to lyse the microorganisms and to form a chemotactic
gradient that induces the migration of iDCs toward the inflammatory
sites; (3) iDCs accumulating at the inflammatory sites phagocytize and
process microbial antigens, differentiate into mDCs, and display the
processed antigenic epitopes on their surfaces in the context of MHC
molecules [21
, 35
]; (4) mDCs down-regulate
receptors for defensins and other chemotactic ligands
[22
, 37
38
39
], and up-regulate CCR7
[39
40
41
], which enables them to migrate away from the
inflammatory sites toward the secondary lymphoid tissues where they
present antigenic epitopes to lymphocytes to initiate antigen-specific
adaptive immune responses [21
, 35
]; (5)
local
defensin gradient may also facilitate the recruitment of T
cells to the inflammatory sites to react to the microorganisms; and (6)
defensins may also help fine-tune host immune reactions against
invading microorganisms by regulating the activation of the classical
complement pathway [14
, 15
]. Apparently,
the greater the number of iDCs recruited into inflammatory sites, the
greater the antigen-specific antimicrobial immune responses.
Analysis of the dose responses of diverse effects of
defensins
reveals that two different effective dose ranges exist. High
concentrations of
defensins (micromolar range) are required to
disrupt the cell membranes of microorganisms or some tumor cells
[1
, 2
, 7
8
9
], to inhibit NADPH
activation [12
, 42
], to interact with
complement C1 [14
, 15
], and to promote the
binding of lipoproteins to vascular matrix [16
]. In
contrast, only low concentrations of
defensins (nanomolar range)
are sufficient for their mitogenic [13
], corticostatic
[11
], and chemotactic activities [10
,
17
]. High doses of
defensins act by forming pore-like
structures within the cell membrane or interacting with negatively
charged molecules, whereas the low-dose effects may be mediated through
specific receptor(s) on target cells. This notion is supported by the
result that HNP-induced migration of both T cells and iDCs is
inhibitable by pretreatment of the target cells with PTX (Table 2)
,
indicating that HNP uses Gi
protein-coupled receptor(s).
Along similar lines, human ß defensins use CC chemokine receptor 6 as
their receptor [20
] and plant defensins also interact
with specific receptors on the target cells [43
].
Although both HNP and human ß defensins selectively chemoattract
human immature DCs, HNP does not use CC chemokine 6 as a receptor (data
not shown). This is not surprising given the fact that HNP and human
ß defensins are selectively chemotactic for naive and memory
CD4+ T cells, respectively. Obviously, it is important to
identify and/or clone the receptor(s) of HNP in order to gain a deeper
understanding of the biology and roles in adaptive immunity of HNP.
The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The publisher or recipient acknowledges right of the U.S. Government to retain a nonexclusive, royalty-free license in and to any copyright covering the article.
Received December 24, 1999; revised February 11, 2000; accepted February 14, 2000.
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J. Exp. Med. 184,695-706
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O. Levy Antimicrobial proteins and peptides: anti-infective molecules of mammalian leukocytes J. Leukoc. Biol., November 1, 2004; 76(5): 909 - 925. [Abstract] [Full Text] [PDF] |
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R. Bals and P.S. Hiemstra Innate immunity in the lung: how epithelial cells fight against respiratory pathogens Eur. Respir. J., February 1, 2004; 23(2): 327 - 333. [Abstract] [Full Text] [PDF] |
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J. Aarbiou, R. M. Verhoosel, S. van Wetering, W. I. de Boer, J. H. J. M. van Krieken, S. V. Litvinov, K. F. Rabe, and P. S. Hiemstra Neutrophil Defensins Enhance Lung Epithelial Wound Closure and Mucin Gene Expression In Vitro Am. J. Respir. Cell Mol. Biol., February 1, 2004; 30(2): 193 - 201. [Abstract] [Full Text] [PDF] |
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G. S. Tjabringa, J. Aarbiou, D. K. Ninaber, J. W. Drijfhout, O. E. Sorensen, N. Borregaard, K. F. Rabe, and P. S. Hiemstra The Antimicrobial Peptide LL-37 Activates Innate Immunity at the Airway Epithelial Surface by Transactivation of the Epidermal Growth Factor Receptor J. Immunol., December 15, 2003; 171(12): 6690 - 6696. [Abstract] [Full Text] [PDF] |
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S. Tanaka, J. C. Edberg, W. Chatham, G. Fassina, and R. P. Kimberly Fc{gamma}RIIIb Allele-Sensitive Release of {alpha}-Defensins: Anti-Neutrophil Cytoplasmic Antibody-Induced Release of Chemotaxins J. Immunol., December 1, 2003; 171(11): 6090 - 6096. [Abstract] [Full Text] [PDF] |
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N. Teleshova, I. Frank, and M. Pope Immunodeficiency virus exploitation of dendritic cells in the early steps of infection J. Leukoc. Biol., November 1, 2003; 74(5): 683 - 690. [Abstract] [Full Text] [PDF] |
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D. Yang, H. F. Rosenberg, Q. Chen, K. D. Dyer, K. Kurosaka, and J. J. Oppenheim Eosinophil-derived neurotoxin (EDN), an antimicrobial protein with chemotactic activities for dendritic cells Blood, November 1, 2003; 102(9): 3396 - 3403. [Abstract] [Full Text] [PDF] |
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J J Oppenheim, A Biragyn, L W Kwak, and D Yang Roles of antimicrobial peptides such as defensins in innate and adaptive immunity Ann Rheum Dis, November 1, 2003; 62(90002): ii17 - 21. [Abstract] [Full Text] [PDF] |
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D. Yang, Q. Chen, D. M. Hoover, P. Staley, K. D. Tucker, J. Lubkowski, and J. J. Oppenheim Many chemokines including CCL20/MIP-3{alpha} display antimicrobial activity J. Leukoc. Biol., September 1, 2003; 74(3): 448 - 455. [Abstract] [Full Text] [PDF] |
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P. S. Grutkoski, C. T. Graeber, Y. P. Lim, A. Ayala, and H. H. Simms {alpha}-Defensin 1 (Human Neutrophil Protein 1) as an Antichemotactic Agent for Human Polymorphonuclear Leukocytes Antimicrob. Agents Chemother., August 1, 2003; 47(8): 2666 - 2668. [Abstract] [Full Text] [PDF] |
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Z. Wu, D. M. Hoover, D. Yang, C. Boulegue, F. Santamaria, J. J. Oppenheim, J. Lubkowski, and W. Lu Engineering disulfide bridges to dissect antimicrobial and chemotactic activities of human {beta}-defensin 3 PNAS, July 22, 2003; 100(15): 8880 - 8885. [Abstract] [Full Text] [PDF] |
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R. Pabst, A. Luhrmann, I. Steinmetz, and T. Tschernig A Single Intratracheal Dose of the Growth Factor Fms-Like Tyrosine Kinase Receptor-3 Ligand Induces a Rapid Differential Increase of Dendritic Cells and Lymphocyte Subsets in Lung Tissue and Bronchoalveolar Lavage, Resulting in an Increased Local Antibody Production J. Immunol., July 1, 2003; 171(1): 325 - 330. [Abstract] [Full Text] [PDF] |
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T. L.-Y. Chang, F. Francois, A. Mosoian, and M. E. Klotman CAF-Mediated Human Immunodeficiency Virus (HIV) Type 1 Transcriptional Inhibition Is Distinct from {alpha}-Defensin-1 HIV Inhibition J. Virol., June 15, 2003; 77(12): 6777 - 6784. [Abstract] [Full Text] [PDF] |
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R. Raqib, P. K. Moly, P. Sarker, F. Qadri, N. H. Alam, M. Mathan, and J. Andersson Persistence of Mucosal Mast Cells and Eosinophils in Shigella-Infected Children Infect. Immun., May 1, 2003; 71(5): 2684 - 2692. [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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A. Obata-Onai, S.-i. Hashimoto, N. Onai, M. Kurachi, S. Nagai, K.-i. Shizuno, T. Nagahata, and K. Matsushima Comprehensive gene expression analysis of human NK cells and CD8+ T lymphocytes Int. Immunol., October 1, 2002; 14(10): 1085 - 1098. [Abstract] [Full Text] [PDF] |
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S. H. Hall, K. G. Hamil, and F. S. French Host Defense Proteins of the Male Reproductive Tract J Androl, September 1, 2002; 23(5): 585 - 597. [Full Text] [PDF] |
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Y. Chen, T. Douglass, E. W. B. Jeffes, Q. Xu, C. C. Williams, N. Arpajirakul, C. Delgado, M. Kleinman, R. Sanchez, Q. Dan, et al. Living T9 glioma cells expressing membrane macrophage colony-stimulating factor produce immediate tumor destruction by polymorphonuclear leukocytes and macrophages via a "paraptosis"-induced pathway that promotes systemic immunity against intracranial T9 gliomas Blood, July 30, 2002; 100(4): 1373 - 1380. [Abstract] [Full Text] [PDF] |
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A. Luhrmann, U. Deiters, J. Skokowa, M. Hanke, J. E. Gessner, P. F. Muhlradt, R. Pabst, and T. Tschernig In Vivo Effects of a Synthetic 2-Kilodalton Macrophage-Activating Lipopeptide of Mycoplasma fermentans after Pulmonary Application Infect. Immun., July 1, 2002; 70(7): 3785 - 3792. [Abstract] [Full Text] [PDF] |
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J. Aarbiou, M. Ertmann, S. van Wetering, P. van Noort, D. Rook, K. F. Rabe, S. V. Litvinov, J. H. J. M. van Krieken, W. I. de Boer, and P. S. Hiemstra Human neutrophil defensins induce lung epithelial cell proliferation in vitro J. Leukoc. Biol., July 1, 2002; 72(1): 167 - 174. [Abstract] [Full Text] [PDF] |
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L. Steinstraesser, B. F. Tack, A. J. Waring, T. Hong, L. M. Boo, M.-H. Fan, D. I. Remick, G. L. Su, R. I. Lehrer, and S. C. Wang Activity of Novispirin G10 against Pseudomonas aeruginosa In Vitro and in Infected Burns Antimicrob. Agents Chemother., June 1, 2002; 46(6): 1837 - 1844. [Abstract] [Full Text] [PDF] |
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C. A. Muller, J. Markovic-Lipkovski, T. Klatt, J. Gamper, G. Schwarz, H. Beck, M. Deeg, H. Kalbacher, S. Widmann, J. T. Wessels, et al. Human {alpha}-Defensins HNPs-1, -2, and -3 in Renal Cell Carcinoma : Influences on Tumor Cell Proliferation Am. J. Pathol., April 1, 2002; 160(4): 1311 - 1324. [Abstract] [Full Text] [PDF] |
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F. P. Paulsen, T. Pufe, U. Schaudig, J. Held-Feindt, J. Lehmann, J.-M. Schroder, and B. N. Tillmann Detection of Natural Peptide Antibiotics in Human Nasolacrimal Ducts Invest. Ophthalmol. Vis. Sci., September 1, 2001; 42(10): 2157 - 2163. [Abstract] [Full Text] [PDF] |
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A. M. Cole, T. Ganz, A. M. Liese, M. D. Burdick, L. Liu, and R. M. Strieter Cutting Edge: IFN-Inducible ELR- CXC Chemokines Display Defensin-Like Antimicrobial Activity J. Immunol., July 15, 2001; 167(2): 623 - 627. [Abstract] [Full Text] [PDF] |
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D. Yang, O. Chertov, and J. J. Oppenheim Participation of mammalian defensins and cathelicidins in anti-microbial immunity: receptors and activities of human defensins and cathelicidin (LL-37) J. Leukoc. Biol., May 1, 2001; 69(5): 691 - 697. [Abstract] [Full Text] |
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De Yang, Q. Chen, A. P. Schmidt, G. M. Anderson, J. M. Wang, J. Wooters, J. J. Oppenheim, and O. Chertov LL-37, the Neutrophil Granule- and Epithelial cell-derived Cathelicidin, Utilizes Formyl Peptide Receptor-like 1 (FPRL1) as a Receptor to Chemoattract Human Peripheral Blood Neutrophils, Monocytes, and T Cells J. Exp. Med., October 2, 2000; 192(7): 1069 - 1074. [Abstract] [Full Text] [PDF] |
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