MINIREVIEW
Multifunctional host defense peptides: Antimicrobial
peptides, the small yet big players in innate and adaptive
immunity
Constance Auvynet
1,2,
* and Yvonne Rosenstein
1
1 Instituto de Biotecnologia, Universidad Nacional Auto
´
noma de Me
´
xico, Cuernavaca, Mor. Mexico
2 FRE 2852, Peptidome de la peau des amphibiens, CNRS ⁄ Universite
´
Pierre et Marie Curie, Paris, France
Introduction
Antimicrobial peptides constitute a heterogeneous
group of peptides with respect to their primary and
secondary structures, their antimicrobial potentials,
their effects on host cells, and the regulation of their
expression. Most antimicrobial peptides are small (12–
50 amino acids), have a positive charge provided by
Arg and Lys residues, and an amphipathic structure
that enables them to interact with bacterial
membranes. Cationic peptides are divided into several
subfamilies, of which the most extensively studied are
the mammalian gene families of antimicrobial peptides,
the cathelicidins and defensins [1–3]. A comprehensive
view of the field can be obtained through recent
reviews that have covered this subject extensively [4–7].

called host defense peptides, participate in multiple aspects of immunity
(inflammation, wound repair, and regulation of the adaptive immune sys-
tem) as well as in maintaining homeostasis. The possibility of utilizing these
multifunctional molecules to effectively combat the ever-growing group of
antibiotic-resistant pathogens has intensified research aimed at improving
their antibiotic activity and therapeutic potential, without the burden of an
exacerbated inflammatory response, but conserving their immunomodula-
tory potential. In this minireview, we focus on the contribution of small
cationic antimicrobial peptides – particularly human cathelicidins and defen-
sins – to the immune response and disease, highlighting recent advances
in our understanding of the roles of these multifunctional molecules.
Abbreviations
CRAMP, murine cathelin-related antimicrobial peptide; EGFR, epidermal growth factor receptor; ET, extracellular trap; GM-CSF, granulocyte–
macrophage colony-stimulating factor; HD, human defensin; hBD, human b-defensin; HNP, human neutrophil peptide (a-defensins); IFN-c,
interferon-c; IL, interleukin; LPS, lipopolysaccharide; NFjB, nuclear factor kappaB; NK, natural killer; SCCE, stratum corneum chymotryptic
enzyme; SCTE, stratum corneum tryptic enzyme; TCF-4, transcription factor-4; TLR, Toll-like receptor; TNF-a, tumor necrosis factor-a; VDR,
vitamin D receptor.
FEBS Journal 276 (2009) 6497–6508 ª 2009 The Authors Journal compilation ª 2009 FEBS 6497
Herein, we have centered our attention on the most
recent findings regarding the transcriptional regulation
of cathelicidins and defensins, and the mechanisms
through which they modulate different facets of immu-
nity and disease.
Defensins are cationic peptides containing six Cys
residues forming three intramolecular disulfide bonds.
On the basis of the position of the six conserved Cys
residues and on sequence identity, members of this
family of peptides have been classified into a-defensins,
b-defensins, and h-defensins. Defensins are widely
expressed [8], and in mammalian species more than

responses [14].
Expression pattern and gene regulation
In general, mature, biologically active peptides require
proteolytic cleavage from a precursor peptide [15]. The
expression pattern of antimicrobial peptides is not uni-
form across species, and within a species it is regulated
by the cellular lineage, the differentiation ⁄ activation
state of the cell, and the tissue type [16]. Some antimi-
crobial peptides are synthesized in the absence of infec-
tion or inflammation, whereas others are upregulated
in response to endogenous or infectious ‘alarm’ signals,
suggesting different functions for these peptides under
different physiological settings. Moreover, differential
proteolytic processing can modulate their activity and,
by extension, their ability to modulate immunity [17].
Consequently, the combination of defense peptides
produced by different cell types in a given tissue can
positively or negatively modify cell functions, ulti-
mately promoting bacterial clearance, albeit not neces-
sarily through direct killing, but through the
establishment of immune cell circuits.
Defensins
Genes for antimicrobial peptides tend to cluster within
a chromosomal region. In the human genome, the
genes encoding most human defensins are grouped
within the same chromosomal region (8p21–23) [18],
suggesting evolution from a single precursor gene as
well as the existence of a master switch to orchestrate
the synthesis of these molecules. However, the genes
encoding the defensin family secreted in epididymis,

AMPs, the small yet big players of immunity C. Auvynet and Y. Rosenstein
6498 FEBS Journal 276 (2009) 6497–6508 ª 2009 The Authors Journal compilation ª 2009 FEBS
Human b-defensins (hBDs) 1–4 show unique as
well as overlapping expression patterns. The hBD-1
b-defensin is constitutively synthesized by epithelia that
are in direct contact with the environment or microbial
flora, such as lung, salivary gland, mammary gland,
prostate, gut, as well as by leukocytes; it is upregulated
by lipopolysaccharide (LPS) and peptidoglycan [24].
Although the expression pattern of hBD2 overlaps
with that of hBD1, it is also present in skin, pancreas,
leukocytes, and bone marrow. In addition to epithelia,
hBD3 has been detected in nonepithelial cells, in the
heart, liver, and placenta [4], and hBD4 mRNA has
been detected in the testis, epididymis, lung tumor tis-
sue [25], and gastric epithelial cells [26]. hBD1 and
hBD2 have predominant antibacterial activity against
Gram-negative bacteria and some fungi, whereas
hBD3 has a broader spectrum and kills many patho-
genic Gram-positive and Gram-negative bacteria and
opportunistic yeasts such as Candida albicans [27].
b-Defensin expression is modulated in response to
bacterial-derived molecules and ⁄ or to cytokines and
chemokines produced by the immune system or dam-
aged cells [16]. In keratinocytes stimulated by bacteria,
interferon-c (IFN-c), tumor necrosis factor-a (TNF-a),
interleukin (IL)-b, IL-17, or IL-22, hBD2 and hBD4
gene expression is upregulated, like that of hBD1 and
hBD3 in airway, intestinal or uterine epithelial cells
[28,29], whereas it is inhibited by retinoic acid [30] and

cathelicidin in the skin. However, LL-37 is susceptible
to proteolytic processing, generating multiple cathelici-
din-derived peptides that are present in normal human
skin. LL-37 actually represents < 20% of the cathelic-
idin-derived peptides, smaller forms of the peptide
being more abundant. These smaller peptides result
from proteolytic processing by two serine proteases
belonging to the tissue kallicrein family: stratum corne-
um tryptic enzyme (SCTE) (kallicrein-5) and stratum
corneum chymotryptic enzyme (SCCE) (kallicrein-7).
Based on its specificity, each enzyme generates a differ-
ent set of peptides. SCTE generates three main pep-
tides (KS30, KS22, and LL29), whereas the cleavage
of LL-37 by SCCE yields two peptides (RK31 and
KR20). SCTE is considered to be the generator of the
cathelicidin-derived antimicrobial activity (KS30, KS22
and LL29 are very potent antimicrobial compounds,
but lack chemotactic activity), and SCCE may be
considered as the inactivator of LL-37, rather than a
generator of antimicrobial peptides [17]. Ultimately,
the relative proportions of these peptides may set the
balance between antimicrobial activity and immuno-
modulatory function.
Expression of defensin-coding and
cathelicidin-coding genes
The final combination of peptides at a specific location
reflects the signaling of pattern ⁄ pathogen-associated
receptors as well as that of other molecules that sense
the environmental conditions. A proof of this was pro-
vided by experiments showing that frogs do not syn-

NFAT binding site overlapping the Pu.1 site. Interest-
ingly, NFAT was found to be associated with the pro-
moter in response to hepatitis C infection, thus
suggesting a correlation between a-defensin expression
and liver fibrosis [45]. In human skin, during wound
healing, the synthesis of antimicrobial peptides by
incoming neutrophils, and notably that of hBD-3, is
induced through an LL-37-mediated mechanism of
transactivation of the epidermal growth factor receptor
[46].
The promoter regions of cathelicidin genes have
consensus binding sites for NFjB, IL-6, acute phase
response factor and IFN-c response element as well
[16]. In mice, murine cathelin-related antimicrobial
peptide (CRAMP) is dependent on hypoxia-inducible
factor-1a, a factor now understood to play a key role
in the bactericidal capacity of phagocytic cells such as
macrophages and neutrophils [47]. In different human
cell types (keratinocytes, monocytes, neutrophils, and
bone marrow-derived macrophages), cathelicidin gene
expression is under the control of vitamin D-respon-
sive elements [48]. In turn, upregulation of the vita-
min D receptor (VDR) and Cyp27B1, the enzyme
that catalyzes the conversion of 25-hydroxyvitamin
D
3
to the active 1,25-hydroxyvitamin D
3
, is depen-
dent on TLR-mediated signals. Moreover, 1,25-hy-

tors (glucocorticoid receptor, retinoic receptor, etc.) is
not restricted to cathelicidins, and that it extends to
other antimicrobial peptides, in particular a-defensins.
Furthermore, this in silico study identified a core set of
transcription factors regulating the transcription of the
majority of antimicrobial peptides considered. The
transcription factors were grouped in tissue specific-
categories, of which the liver-specific, neuron-specific
and nuclear hormone-specific factors occupied the first
positions, underscoring new functions for antimicrobial
peptides in energy metabolism and neuroendocrine
regulation [52], in addition to their role in immunity.
Immunomodulatory properties of
antimicrobial peptides
By disrupting bacterial membranes, antimicrobial pep-
tides participate as direct effectors of innate immunity.
Multiple antimicrobial peptides are simultaneously
present at the same site, and they are thought to
work in concert, to effectively fight infection. It has
frequently been argued that the minimal inhibitory con-
centration of antimicrobial peptides needed to effec-
tively combat microbial infection is rarely found in
in vivo conditions, despite the fact that antimicrobial
peptide gene expression is mostly under the control of
innate immunity-related transcription factors. However,
in addition to the concentration of these natural antibi-
otics, the resistance of the microbial membrane (i.e. the
target of the antimicrobial peptides) in a given ionic
environment is the counterpart to effectiveness of anti-
microbial activity. In support of this, it has recently

derived alarmins, minimizing tissue damage.
Data from experiments with knockout and trans-
genic mice highlight the direct antimicrobial effect of
antimicrobial peptides [7,16]. However, given the cen-
tral role that antimicrobial peptides seem to play in
the outcome of an infection ⁄ injury, it is surprising to
see that all knockout mice lacking antimicrobial pep-
tides are quite healthy, with only modest alterations in
susceptibility to specific infectious agents. For example,
mice lacking b-defensin-1 are inefficient at clearing
Haemophilus influenzae from their lungs [56], and
CRAMP-deficient mice are impaired in their ability to
clear skin infections caused by group A Streptococcus
[57]. These results underline the fact that antimicrobial
peptides work in concert, and that their ranges of
activity frequently overlap.
Apart from efficient antimicrobial activity, antimi-
crobial peptides modulate immunity. They seem to
participate in every facet of it, by boosting the immune
response to prevent infection, and also by suppressing
other proinflammatory responses to avoid uncontrolled
inflammation. Furthermore, some antimicrobial pep-
tides synergize with cytokines and modify their immuno-
modulatory activity.
Chemotactic activity
In addition to their direct microbicidal activity, antimi-
crobial peptides are chemotactic for leukocytes and
other nonimmune cells at nanomolar concentrations.
Despite a certain overlap, antimicrobial peptides work
in concert, as they complement each other to direct

locomotion and arrival of different cohorts of cells to
the site of injury, antimicrobial peptides indirectly
favor chemotaxis by inducing or increasing the secre-
tion of chemokines. For example, LL-37 has been
shown to induce IL-8 release by lung epithelial cell
lines [59,60], and human defensins HNP1–3 also favor
the recruitment of neutrophils by inducing the activa-
tion and degranulation of mast cells, augmenting neu-
trophil influx and further stimulating the transcription
and production of IL-8 by bronchial epithelial cells
[61–64].
Antimicrobial peptide-induced chemotaxis is pre-
sumably mediated through G-protein-coupled recep-
tors, as pretreatment of the cells with pertussis toxin
or phospholipase C, phosphoinositide-3-kinase and
Rho kinase inhibitors abolishes cell migration [65].
According to the peptide and the cell, several receptors
have been identified. LL-37, like the frog peptides tem-
porin A and probably Drs S9, attracts cells through
formyl peptide receptor-like-1, whereas defensins
hBD2 and hBD3 use CC-chemokine receptor-6, pres-
ent on memory T-cells, immature dendritic cells, and
human colonic epithelial cells [66–69]. CC-chemokine
receptor-6 is also the receptor for macrophage inflam-
matory protein-3a, a chemokine involved in homeo-
static lymphocyte homing as well as in epithelial cell
migration, further suggesting a function for hBD2
in healing and protection of the intestinal epithelial
barrier [70].
Proinflammatory and anti-inflammatory signals

[72], increase the production of TNF-a and IL-1b, and
decrease the production of IL-10 by monocytes
[61,62,73]. Furthermore, as an endogenous ligand for
TLR-4, b-defensin-2 activates immature dendritic cells
through TLR-4-dependent mechanisms, triggering a
robust Th1 response [74]. Consistent with their role in
wounding, b-defensin-mediated signals positively regu-
late the expression of matrix metalloproteinase genes
and negatively regulate that of tissue inhibitor of
matrix metalloproteinase genes, thus modulating tissue
repair [75,76]. LL-37 induces the release of IL-1b, IL-
8, TNF-a, IL-6 and granulocyte–macrophage colony-
stimulating factor (GM-CSF) by keratinocytes, and of
TNF-a and IL-6 by immature dendritic cells [58,77].
Moreover, LL-37 and GM-CSF synergize, as the pres-
ence of GM-CSF augments LL-37-mediated mitogen-
activated protein kinase activation and reduces the
amount of LL-37 required for this activation and for
cytokine production [78,79].
Cathelicidins function as anti-inflammatory mole-
cules as well. In in vivo models, administration of
LL-37 protects mice and rats from LPS-mediated
lethality [60,80]. Indeed, LL-37 binds and neutralizes
LPS, possibly by dissociation of LPS aggregates, limit-
ing the extent of inflammation [60,81–84]. Addition-
ally, cathelicidin abrogates the expression of
proinflammatory molecules such as TNF-a and IL-6
and the nuclear translocation of NFjB p50 ⁄ p65
induced by TLR-2 and TLR-4 in response to lipoteic
acid and LPS, respectively, through a partially defined

ful proinflammatory responses without losing the
beneficial infection-fighting components of host innate
defenses, are desirable tools for antisepsis therapies.
Defensins play the same dual role as cathelicidins.
The activation of TLR-4, mediated through murine
b-defensin-2, leads to atypical death of dendritic cells,
through upregulation of membrane-bound TNF-a and
tumor necrosis factor receptor 2. This suggests that
b-defensins participate in the triggering of an immune
response and in the natural process of elimination of
activated antigen-presenting cells and termination of
the immune response [90].
Healing
Infection and injury provoke tissue damage. Immedi-
ately after injury, innate immune cells, mostly neu-
trophils and macrophages, together with antimicrobial
peptides, produced by immune cells or secreted by
local cells, will take care of microbe clearance and
removal of debris. Other cells, such as T-lymphocytes,
secrete cytokines and chemokines that will further
activate macrophages and induce inflammation and
vasodilatation, and enhance vessel permeability. Tissue
AMPs, the small yet big players of immunity C. Auvynet and Y. Rosenstein
6502 FEBS Journal 276 (2009) 6497–6508 ª 2009 The Authors Journal compilation ª 2009 FEBS
regeneration requires multiple events. Following
removal of bacteria and debris, the release of growth
factors will promote the migration and proliferation of
fibroblasts, which will deposit the extracellular matrix
over which epithelial cells will crawl and cover the
wound bed [91].

tube formation [96], accelerating wound closure. LL-37
may also have antifibrotic activity during the wound
repair process, as it inhibits baseline and transforming
growth factor-b-induced collagen expression at nanom-
olar concentrations, through an extracellular signal-
related kinase-dependent and G-protein-dependent
pathway [97].
These data regarding the role of antimicrobial pep-
tides in wounding provide evidence for their dual role;
they serve as sentinels and they actively participate in
tissue regeneration. Whether noninducible antimicro-
bial peptides function in a similar way during infec-
tion, under normal conditions or during development
is an attractive possibility. In conclusion, the multiple,
yet sometimes opposite, functions of antimicrobial
peptides are complementary, and they control homeo-
stasis through complex regulatory loops that involve
different cells responding to multiple signaling path-
ways.
Antimicrobial peptides and disease
Dysregulated production of antimicrobial peptides is
associated with disease. As we recognize that these
molecules are multifunctional and that they modulate
multiple events, the list of diseases in which anti-
microbial peptides participate is growing. Throughout
previous sections of this minireview, we have pointed
to the participation of antimicrobial peptides in several
diseases. In this section, we will highlight recent data
on psoriasis, rosacea, atopic dermatitis and Crohn’s
disease.

gene expression. Moreover, Bcl-3 silencing upregulates
the 1,25-dihydroxyvitamin D
3
-dependent production of
cathelicidin in keratinocytes, and 1,25-dihydroxyvita-
min D
3
suppresses Bcl-3 expression [100]. In addition,
Bcl-3 synthesis is upregulated in the presence of IL-4
[101], thus generating a negative feedback loop that
will reduce the cathelicidin concentration, favoring
skin infections and chronic inflammation.
C. Auvynet and Y. Rosenstein AMPs, the small yet big players of immunity
FEBS Journal 276 (2009) 6497–6508 ª 2009 The Authors Journal compilation ª 2009 FEBS 6503
Unlike atopic dermatitis, psoriasis, a common auto-
immune disease of the skin, results partially cathelici-
din overproduction. By binding to damaged or
apoptotic skin cells self-DNA, cathelicidin converts it
into aggregated and condensed structures. That will be
delivered to plasmocytoid dendritic cells. These, in
turn, will infiltrate the psoriatic skin, triggering en-
dosomal TLR-9 and subsequent IFN-c production,
thus driving autoimmune skin inflammation [102].
Patients with rosacea have abnormal inflammation
and vascular reactivity in facial skin. These individuals
have high levels of cathelicidin and higher levels of the
enzyme that processes the propeptide into the LL-37
biologically active peptide and of other unusual iso-
forms of the peptide. The current thinking is that, at
least partially, the chronic inflammation results from

repair. These pleiotropic effects reflect the diversity of
effector molecules and their targets, as well as the
sometimes overlapping, yet very specific, functions.
Through elaborate feedback mechanisms, they control
immune cells as well as nonimmune cells, link innate
immunity to adaptive immunity, and maintain homeo-
stasis. Alterations in their physiological concentrations
correlate with disease. Their antimicrobial activity,
immunomodulatory functions, adjuvant properties and
low toxicity make antimicrobial peptides the object of
intense investigation in order to develop new therapeu-
tic agents with specific activities. A deeper understand-
ing of the signaling pathways underlining these effects
and of the physiological processes that are controlled
by antimicrobial peptides will help in the better exploi-
tation of the potential use of these peptides.
Acknowledgements
We thank Drs L. Perez, G. Pedraza, Claire Lacombe
and G. Corzo for their helpful discussions and com-
ments, and S. Ainsworth for her librarian support.
Work in the Y. Rosenstein laboratory is supported by
CONACyT and DGAPA ⁄ UNAM, Mexico.
References
1 Selsted ME & Ouellette AJ (2005) Mammalian defen-
sins in the antimicrobial immune response. Nat Immu-
nol 6, 551–557.
2 Zasloff M (2002) Antimicrobial peptides of multicellu-
lar organisms. Nature 415, 389–395.
3 Hancock RE (2001) Cationic peptides: effectors in
innate immunity and novel antimicrobials. Lancet

structure, function and evolution. Curr Protein Pept
Sci 6, 23–34.
13 Zanetti M (2005) The role of cathelicidins in the innate
host defenses of mammals. Curr Issues Mol Biol 7,
179–196.
14 Zaiou M & Gallo RL (2002) Cathelicidins, essential
gene-encoded mammalian antibiotics. J Mol Med 80 ,
549–561.
15 Uzzell T, Stolzenberg ED, Shinnar AE & Zasloff M
(2003) Hagfish intestinal antimicrobial peptides are
ancient cathelicidins. Peptides 24, 1655–1667.
16 Yang D, Biragyn A, Hoover DM, Lubkowski J &
Oppenheim JJ (2004) Multiple roles of antimicrobial
defensins, cathelicidins, and eosinophil-derived neuro-
toxin in host defense. Annu Rev Immunol 22, 181–215.
17 Yamasaki K, Schauber J, Coda A, Lin H, Dorschner
RA, Schechter NM, Bonnart C, Descargues P,
Hovnanian A & Gallo RL (2006) Kallikrein-mediated
proteolysis regulates the antimicrobial effects of
cathelicidins in skin. FASEB J 20, 2068–2080.
18 Schutte BC, Mitros JP, Bartlett JA, Walters JD, Jia
HP, Welsh MJ, Casavant TL & McCray PB Jr (2002)
Discovery of five conserved beta-defensin gene clusters
using a computational search strategy. Proc Natl Acad
Sci USA 99, 2129–2133.
19 Rodriguez-Jimenez FJ, Krause A, Schulz S, Forss-
mann WG, Conejo-Garcia JR, Schreeb R & Motzkus
D (2003) Distribution of new human beta-defensin
genes clustered on chromosome 20 in functionally dif-
ferent segments of epididymis. Genomics 81, 175–183.

PS & Nibbering PH (2002) Expression of beta-defensin
1 and 2 mRNA by human monocytes, macrophages
and dendritic cells. Immunology 106, 517–525.
29 Brown KL & Hancock RE (2006) Cationic host defense
(antimicrobial) peptides. Curr Opin Immunol
18, 24–30.
30 Harder J, Meyer-Hoffert U, Wehkamp K, Schwichten-
berg L & Schroder JM (2004) Differential gene induc-
tion of human beta-defensins (hBD-1, -2, -3, and -4) in
keratinocytes is inhibited by retinoic acid. J Invest
Dermatol 123, 522–529.
31 Bick RJ, Poindexter BJ, Bhat S, Gulati S, Buja M &
Milner SM (2004) Effects of cytokines and heat shock
on defensin levels of cultured keratinocytes. Burns 30,
329–333.
32 Braff MH & Gallo RL (2006) Antimicrobial peptides:
an essential component of the skin defensive barrier.
Curr Top Microbiol Immunol 306, 91–110.
33 Frohm M, Gunne H, Bergman AC, Agerberth B,
Bergman T, Boman A, Liden S, Jornvall H & Boman
HG (1996) Biochemical and antibacterial analysis of
human wound and blister fluid. Eur J Biochem 237,
86–92.
34 Dorschner RA, Pestonjamasp VK, Tamakuwala S,
Ohtake T, Rudisill J, Nizet V, Agerberth B,
Gudmundsson GH & Gallo RL (2001) Cutaneous
injury induces the release of cathelicidin anti-microbial
peptides active against group A Streptococcus.
J Invest Dermatol 117, 91–97.
35 Sorensen OE, Cowland JB, Theilgaard-Monch K, Liu

(HBD-1) expression in the intestinal epithelial cells.
Cell Microbiol 10, 2520–2537.
41 Mangoni ML, Miele R, Renda TG, Barra D &
Simmaco M (2001) The synthesis of antimicrobial
peptides in the skin of Rana esculenta is stimulated by
microorganisms. FASEB J 15, 1431–1432.
42 van Es JH, Jay P, Gregorieff A, van Gijn ME,
Jonkheer S, Hatzis P, Thiele A, van den Born M,
Begthel H, Brabletz T et al. (2005) Wnt signalling
induces maturation of Paneth cells in intestinal crypts.
Nat Cell Biol 7, 381–386.
43 Wehkamp J, Wang G, Kubler I, Nuding S, Gregorieff
A, Schnabel A, Kays RJ, Fellermann K, Burk O,
Schwab M et al. (2007) The Paneth cell alpha-defensin
deficiency of ileal Crohn’s disease is linked to
Wnt ⁄ Tcf-4. J Immunol 179, 3109–3118.
44 Koslowski MJ, Kubler I, Chamaillard M, Schaeffeler
E, Reinisch W, Wang G, Beisner J, Teml A, Peyrin-
Biroulet L, Winter S et al. (2009) Genetic variants of
Wnt transcription factor TCF-4 (TCF7L2) putative
promoter region are associated with small intestinal
Crohn’s disease. PLoS ONE 4, e4496.
45 Aceti A, Mangoni ML, Pasquazzi C, Fiocco D,
Marangi M, Miele R, Zechini B, Borro M, Versace I
& Simmaco M (2006) Alpha-defensin increase in
peripheral blood mononuclear cells from patients with
hepatitis C virus chronic infection. J Viral Hepatol 13,
821–827.
46 Sorensen OE, Thapa DR, Roupe KM, Valore EV,
Sjobring U, Roberts AA, Schmidtchen A & Ganz T

53 Dorschner RA, Lopez-Garcia B, Peschel A, Kraus D,
Morikawa K, Nizet V & Gallo RL (2006) The mamma-
lian ionic environment dictates microbial susceptibility
to antimicrobial defense peptides. FASEB J 20, 35–42.
54 Wartha F, Beiter K, Normark S & Henriques-Normark
B (2007) Neutrophil extracellular traps: casting the
NET over pathogenesis. Curr Opin Microbiol 10, 52–56.
55 von Kockritz-Blickwede M & Nizet V (2009) Innate
immunity turned inside-out: antimicrobial defense by
phagocyte extracellular traps. J Mol Med 87, 775–783.
56 Moser C, Weiner DJ, Lysenko E, Bals R, Weiser JN
& Wilson JM (2002) beta-Defensin 1 contributes to
pulmonary innate immunity in mice. Infect Immun 70,
3068–3072.
57 Nizet V, Ohtake T, Lauth X, Trowbridge J, Rudisill J,
Dorschner RA, Pestonjamasp V, Piraino J, Huttner K
& Gallo RL (2001) Innate antimicrobial peptide pro-
tects the skin from invasive bacterial infection. Nature
414, 454–457.
58 Davidson DJ, Currie AJ, Reid GS, Bowdish DM,
MacDonald KL, Ma RC, Hancock RE & Speert DP
(2004) The cationic antimicrobial peptide LL-37 modu-
lates dendritic cell differentiation and dendritic cell-
induced T cell polarization. J Immunol 172, 1146–1156.
59 Tjabringa GS, Aarbiou J, Ninaber DK, Drijfhout JW,
Sorensen OE, Borregaard N, Rabe KF & Hiemstra PS
(2003) The antimicrobial peptide LL-37 activates
innate immunity at the airway epithelial surface by
transactivation of the epidermal growth factor recep-
tor. J Immunol 171, 6690–6696.

CAP37 ⁄ azurocidin as T-cell chemoattractant proteins
released from interleukin-8-stimulated neutrophils.
J Biol Chem 271, 2935–2940.
67 Yang D, Chen Q, Chertov O & Oppenheim JJ (2000)
Human neutrophil defensins selectively chemoattract
naive T and immature dendritic cells. J Leukoc Biol
68, 9–14.
68 Chen T, Tang L & Shaw C (2003) Identification of
three novel Phyllomedusa sauvagei dermaseptins
(sVI–sVIII) by cloning from a skin secretion-derived
cDNA library. Regul Pept 116 , 139–146.
69 Auvynet C, El Amri C, Lacombe C, Bruston F,
Bourdais J, Nicolas P & Rosenstein Y (2008) Struc-
tural requirements for antimicrobial versus chemo-
attractant activities for dermaseptin S9. FEBS J 275,
4134–4151.
70 Otte JM, Werner I, Brand S, Chromik AM, Schmitz
F, Kleine M & Schmidt WE (2008) Human beta defen-
sin 2 promotes intestinal wound healing in vitro. J Cell
Biochem 104, 2286–2297.
71 Chen X, Niyonsaba F, Ushio H, Hara M, Yokoi H,
Matsumoto K, Saito H, Nagaoka I, Ikeda S, Okumura
K et al. (2007) Antimicrobial peptides human beta-
defensin (hBD)-3 and hBD-4 activate mast cells and
increase skin vascular permeability. Eur J Immunol 37,
434–444.
72 Prohaszka Z, Nemet K, Csermely P, Hudecz F, Mezo
G & Fust G (1997) Defensins purified from human
granulocytes bind C1q and activate the classical com-
plement pathway like the transmembrane glycoprotein

Regulation of myeloid development and function by
colony stimulating factors. Dev Comp Immunol 28,
509–554.
79 Bowdish DM, Davidson DJ, Speert DP & Hancock
RE (2004) The human cationic peptide LL-37 induces
activation of the extracellular signal-regulated kinase
and p38 kinase pathways in primary human mono-
cytes. J Immunol 172, 3758–3765.
80 Cirioni O, Giacometti A, Ghiselli R, Bergnach C,
Orlando F, Silvestri C, Mocchegiani F, Licci A,
Skerlavaj B, Rocchi M et al. (2006) LL-37 protects
rats against lethal sepsis caused by gram-negative
bacteria. Antimicrob Agents Chemother 50, 1672–1679.
81 Scott MG, Vreugdenhil AC, Buurman WA, Hancock
RE & Gold MR (2000) Cutting edge: cationic antimicro-
bial peptides block the binding of lipopolysaccharide
(LPS) to LPS binding protein. J Immunol 164, 549–553.
82 Oppenheim JJ & Yang D (2005) Alarmins: chemo-
tactic activators of immune responses. Curr Opin
Immunol 17, 359–365.
83 Rosenfeld Y, Papo N & Shai Y (2006) Endotoxin
(lipopolysaccharide) neutralization by innate immunity
host-defense peptides. Peptide properties and plausible
modes of action. J Biol Chem 281, 1636–1643.
84 Bhunia A, Mohanram H & Bhattacharjya S (2009)
Lipopolysaccharide bound structures of the active
fragments of fowlicidin-1, a cathelicidin family of anti-
microbial and antiendotoxic peptide from chicken,
determined by transferred nuclear overhauser effect
spectroscopy. Biopolymers 92, 9–22.

Young HA & Olkhanud P (2008) Murine beta-
defensin 2 promotes TLR-4 ⁄ MyD88-mediated and
NF-kappaB-dependent atypical death of APCs via
activation of TNFR2. J Leukoc Biol 83, 998–1008.
91 Martin P & Leibovich SJ (2005) Inflammatory cells
during wound repair: the good, the bad and the ugly.
Trends Cell Biol 15, 599–607.
92 Heilborn JD, Nilsson MF, Kratz G, Weber G, Soren-
sen O, Borregaard N & Stahle-Backdahl M (2003) The
cathelicidin anti-microbial peptide LL-37 is involved in
re-epithelialization of human skin wounds and is lack-
ing in chronic ulcer epithelium. J Invest Dermatol 120,
379–389.
93 Tokumaru S, Sayama K, Shirakata Y, Komatsuzawa
H, Ouhara K, Hanakawa Y, Yahata Y, Dai X,
Tohyama M, Nagai H et al. (2005) Induction of
keratinocyte migration via transactivation of the
epidermal growth factor receptor by the antimicrobial
peptide LL-37. J Immunol 175, 4662–4668.
94 Koczulla R, von Degenfeld G, Kupatt C, Krotz F,
Zahler S, Gloe T, Issbrucker K, Unterberger P, Zaiou
M, Lebherz C et al. (2003) An angiogenic role for the
human peptide antibiotic LL-37 ⁄ hCAP-18. J Clin
Invest 111, 1665–1672.
95 Braff MH, Zaiou M, Fierer J, Nizet V & Gallo RL
(2005) Keratinocyte production of cathelicidin pro-
vides direct activity against bacterial skin pathogens.
Infect Immun 73 , 6771–6781.
96 Baroni A, Donnarumma G, Paoletti I, Longanesi-
Cattani I, Bifulco K, Tufano MA & Carriero MV

564–569.
103 Yamasaki K, Di Nardo A, Bardan A, Murakami M,
Ohtake T, Coda A, Dorschner RA, Bonnart C,
Descargues P, Hovnanian A et al. (2007) Increased
serine protease activity and cathelicidin promotes skin
inflammation in rosacea. Nat Med 13, 975–980.
104 Gersemann M, Wehkamp J, Fellermann K & Stange
EF (2008) Crohn’s disease – defect in innate defence.
World J Gastroenterol 14, 5499–5503.
AMPs, the small yet big players of immunity C. Auvynet and Y. Rosenstein
6508 FEBS Journal 276 (2009) 6497–6508 ª 2009 The Authors Journal compilation ª 2009 FEBS