Se revelan los diferentes roles de los Péptidos Naturales Antimicrobianos

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14:1649–1660.
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nantly by the ability of these agents to effects that sex steroid hormones have gen receptors: dissociation from transcriptional
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What is the real role of antimicrobial proteins and peptides in inflammation
paralleled the evolving methodology of
polypeptides that can mediate several protein biochemistry and purification,
and molecular biology. In this histori-
other inflammatory responses? cal context, the initial focus remained
on the antibacterial action of newly iso-
Peter Elsbach lated proteins and peptides, reflecting
an ongoing search for new antibiotics
Department of Medicine, New York University School of Medicine, New York, New York, USA
and the relative ease of conducting
bioassays of bacterial viability (2, 3).
Antimicrobial peptides are effector molecules of innate immunity with
microbicidal and pro- or anti-inflammatory activities. Their role is now Discovery of proteins and
widening following evidence that one such multifunctional peptide, polypeptides with antibacterial
LL-37, induces angiogenesis, a process essential for host defense, wound properties
healing, and tissue repair (see related article beginning on page 1665). Numerous proteins and polypeptides
with antimicrobial activity in vitro
J. Clin. Invest. 111:1643–1645 (2003). doi:10.1172/JCI200318761. have now been isolated and/or cloned
from a broad range of both simple
The last two decades have heralded implicated in many aspects of the and complex organisms, including
impressive progress in the identifica- host response to infection and other humans. Thus, endogenous-polypep-
tion of a broad array of structurally inflammatory stimuli. tide antibiotics became prominent
and functionally diverse polypeptides Almost half a century ago, Hirsch targets in the study of antimicrobial
described the antimicrobial properties host defenses per se and also as poten-
Address correspondence to: Peter Elsbach,
of phagocytin, a crude protein fraction tial pharmacologic agents (3). Whole
Department of Medicine, New York of polymorphonuclear leukocytes (1), families of such gene products have
University School of Medicine, 550 First thereby setting the stage for a growing been identified in plants, insects, and
Avenue, New York, New York 10016, USA. interest in the biologic activities of pro- other animals (4) in settings that are
Phone: (212) 263-5633; Fax: (212) 263-3952;
E-mail: elsbap01@mcrcr.med.nyu.edu. tein components of inflammatory consistent with prominent roles in
Conflict of interest: The author has declared cells. The subsequent exploration of innate immunity. How well have these
that no conflict of interest exists. the functional capabilities of defined roles been defined so far?
The Journal of Clinical Investigation | June 2003 | Volume 111 | Number 11 1643

2. in vivo events where multiple agonists
and antagonists, at different concen-
trations and with different affinities,
compete for the same targets.
Whatever the primary function of
these peptides, the study by Koczulla et
al. (6) adds to the growing evidence that
polypeptides produced, stored, and
secreted by inflammatory and epithelial
lining cells may have more than one
Figure 1 role in the complex innate immune
Functions of “antimicrobial” polypeptides in innate immunity. responses of the host. This recognition
raises new issues: much of the interest
in the pursuit of these polypeptides is
The initial demonstration of antimi- hCAP-18 stimulate angiogenesis both linked to the hope that synthetic or
crobial activity of isolated polypep- in vitro and in vivo (6). The proliferative recombinant derivatives of bioactive
tides in vitro, often under very artifi- effect on endothelial cells and vessel for- polypeptides, such as LL-37/hCAP-18,
cial laboratory conditions and against mation is convincingly demonstrated may have a future as administered
nonpathogenic strains of bacteria, did under tissue culture conditions. These agents for the treatment of infection
not establish whether such polypep- effects are also manifest in vivo: admin- and its sequelae. However, if such
tides played a prominent role in vivo. istration of LL-37 was shown to stimu- agents participate in more than one
Moreover, since these polypeptides do late capillary formation in a rabbit hind- biologic activity, possibly at different
not act alone and many share the limb model of ischemia, and mice stages in an inflammatory process, the
apparent molecular determinants of deficient in the murine analog of evaluation of their usefulness and safe-
antimicrobial activity, elucidation of LL-37/hCAP-18 demonstrated less neo- ty becomes accordingly more elaborate.
their role in a complex mix in vivo has vascularization of skin lesions than Is it reasonable, then, to anticipate the
remained elusive. wild-type controls. Both the chemoat- addition of such bioactive substances
tractant and the angiogenic actions of to the pharmacopoeia as treatments of
Polypeptides with antimicrobial and LL-37 are thought to be receptor-medi- complex clinical disorders? Notwith-
other biologic activities ated by interaction with formyl peptide standing the unknowns sketched here
Uncertainty grew concerning the receptor–like 1, found on macrophages, that require clarification, the answer is
actions and effects of individual neutrophils, and subsets of lympho- probably yes.
polypeptides after several were found cytes (6). It is particularly interesting Recent reports suggest a role for a
to possess other biologic activities, that upon exposure of human umbili- cathelicidin common to both mice and
apparently unrelated to their antimi- cal cord endothelial cells to human humans, in addition to other endoge-
crobial actions (Figure 1). For example, serum (10%), which was previously nous polypeptides with antibacterial
α-defensins, at concentrations far shown to inhibit the antimicrobial activity, in providing protection
lower than are required for their activity and anti–host cell cytotoxic against skin infections (10–12). Other
antimicrobial action, are capable of action of LL-37 (6), the angiogenic activ- administered proteins and peptides
several other functions such as chemo- ity of LL-37 was unchanged. have been shown to protect animals
tactic and corticostatin-like actions (5). The angiogenic activity of exogenous against systemic infections (3, 13).
In this issue of the JCI, Koczulla et al. LL-37, as demonstrated in the animal When disease and/or treatment
(6) identify yet another novel biologic experiments, does not reveal whether deplete host stores of proteins and pep-
activity of the polypeptide LL-37/ endogenous LL-37 participates in the tides with defense functions and
hCAP-18, initially described as an regulation of neovascularization by impair or overwhelm their production
antimicrobial member of the catheli- the many other angiogenic factors that by both myeloid and epithelial cells,
cidin family (7). Cathelicidins, first iso- operate in vivo. Also, what governs the replenishment with exogenous analogs
lated from polymorphonuclear leuko- release of the active peptide from its may well become an important adjunc-
cytes, are also constituents of lining precursor during inflammation is tive therapy. This can be envisioned, for
epithelial cells (6). Proteolytic cleavage largely unknown. example, in cases of otherwise healthy
of cathelicidin proforms is required to The recent report that the ribonucle- children with severe pediatric bacterial
free the potent antibacterial activity of ase angiogenin, a component of spe- infections that do not respond to avail-
the C-terminal peptide LL-37/hCAP-18. cialized epithelial cells of the small able antibiotics (14, 15).
The uncleaved proform is devoid of intestinal crypt known as Paneth cells,
1. Hirsch, J.G. 1956. Phagocytin: a bactericidal sub-
antibacterial activity. However, at sub- is also microbicidal (9) further illus- stance from polymorphonuclear leukocytes.
nanomolar concentrations, it is capable trates that such agents may be multi- J. Exp. Med. 103:589–621.
of blocking the bioactivity of endotoxin functional. Obviously, it is a formidable 2. Ganz, T., and Weiss, J. 1997. Antimicrobial
peptides of phagocytes and epithelia. Semin.
(8). Koczulla et al. now show that µg/ml task to define the (patho)physiologic Hematol. 34:343–354.
concentrations of synthetic LL-37/ contribution of any individual agent to 3. Elsbach, P., Weiss, J., and Levy, O. 1999. Oxygen-
1644 The Journal of Clinical Investigation | June 2003 | Volume 111 | Number 11

3. independent antimicrobial systems of phago- 7. Zanetti, M., Gennaro, R., Scocchi, M., and 12. Nizet, V., et al. 2001. Innate antimicrobial peptide
cytes. In Inflammation. Basic principles and clinical Skerlavaj, B. 2000. Structure and biology of cathe- protects the skin from invasive bacterial infec-
correlates. 3rd edition. J. Gallin and R. Snyderman, licidins. Adv. Exp. Med. Biol. 479:203–218. tion. Nature. 414:454–457.
editors. Lippincott-Raven. Philadelphia, Pennsyl- 8. Zarember, K.A., et al. 2002. Host defense func- 13. Levy, O. 2002. Therapeutic potential of the bac-
vania, USA. 801–817. tions of proteolytically processed and parent tericidal/permeability-increasing protein. Expert
4. Hoffmann, J.A., Kafatos, F.C., Janeway, C.A., and (unprocessed) cathelicidins of rabbit granulo- Opin. Investig. Drugs. 11:159–167.
Ezekowitz, R.A. 1999. Phylogenetic perspectives cytes. Infect. Immun. 70:569–576. 14. Levy, O., et al. 1999. Impaired innate immunity in
in innate immunity. Science. 284:1313–1318. 9. Ganz, T. 2003. Angiogenin: an antimicrobial the newborn: newborn neutrophils are deficient
5. Bateman, A., Singh, A., Shustik, C., Mars, W.M., ribonuclease. Nat. Immunol. 4:213–214. in bactericidal/permeability-increasing protein.
and Solomon, S. 1991. The isolation and identi- 10. Ong, P.Y., et al. 2002. Endogenous antimicrobial Pediatrics. 104:1327–1333.
fication of multiple forms of the neutrophil gran- peptides and skin infections in atopic dermatitis. 15. Levin, M., et al. 2000. Recombinant bacterici-
ule peptides from human leukemic cells. J. Biol. N. Engl. J. Med. 347:1151–1160. dal/permeability-increasing protein (rBPI21) as
Chem. 266:7524–7530. 11. Cole, A.M., et al. 2001. Inhibition of neutrophil adjunctive treatment for children with severe
6. Koczulla, R., et al. 2003. An angiogenic role for the elastase prevents cathelicidin activation and meningococcal sepsis: a randomised trial. rBPI21
human peptide antibiotic LL-37/hCAP-18. J. Clin. impairs clearance of bacteria from wounds. Blood. Meningococcal Sepsis Study Group. Lancet.
Invest. 111:1665–1672. doi:10.1172/JCI200317545. 97:297–304. 356:961–967.
Functionally mature virus-specific CD8+ immunity at the fetomaternal inter-
face. The most potent of these involve
T memory cells in congenitally infected local placental production of trypto-
phan metabolites (4) and IL-10 (5),
newborns: proof of principle which inhibit T cell activation and
for neonatal vaccination? proliferation, and expression of FasL,
which eliminates activated T cells (6).
P.G. Holt A second tier of immunomodulatory
mechanisms selectively dampens Th1
Telethon Institute for Child Health Research and Centre for Child Health Research, Faculty of immunity via local production of a
Medicine and Dentistry, University of Western Australia, Perth, Western Australia, Australia range of molecules that are Th2
trophic and/or Th1 inhibitory. These
The presence in newborns of a mature and functional CD8+ T cell include production by placental tro-
response to congenital cytomegalovirus infection (see related article phoblasts of IL-10 and prostaglandin
beginning on page 1747) suggests that the machinery necessary to E2, which drive Th2 switching (5, 7),
prime such responses is present in utero and raises questions related and progesterone, which inhibits
to neonatal vaccination. IFN-γ gene transcription (8). Collec-
tively, these mechanisms attenuate
J. Clin. Invest. 111:1645–1647 (2003). doi:10.1172/JCI200318805. fetal capacity to develop active immu-
nity and bias any responses that
In this issue of the JCI, Marchant et al. Susceptibility to infectious disease escape immunosuppression toward
(1) report the presence of functional- during infancy the Th2 phenotype.
ly mature cytolytic CD8+ T lympho- Increased susceptibility to infectious Survival in the microbiologically
cytes in newborns with congenital diseases is an inescapable fact of neona- hostile postnatal environment neces-
cytomegalovirus (HCMV) infection. tal life and is generally ascribed to sitates upregulation of immune (in
This finding adds to the growing developmentally related deficiencies in particular Th1) functions, which is
body of evidence suggesting that immune function, which are incom- mediated via microbial pattern recog-
intrauterine antigenic stimulation pletely understood. Recent advances in nition receptors (9). However, the post-
has the potential to elicit protective developmental immunology have pro- natal maturation of Th1 competence
immunity in the fetus, which persists vided fresh insight into this issue. Of proceeds relatively slowly between
into the newborn period. This has particular relevance are studies investi- birth and weaning, and this appears to
important implications in relation to gating the mechanisms that facilitate underlie the generally attenuated
infant vaccine development, but sig- fetal survival in the face of continuous capacity of infants to efficiently gener-
nificant questions remain to be maternal immune surveillance. This ate CD4+ T cell memory to antigens in
answered before this potential can be body of research (reviewed in ref. 2) has or on pathogens and in response to
fruitfully exploited. demonstrated that Th1-type cytokines vaccines (10, 11). This may be attribut-
(especially IFN-γ) are exquisitely toxic able in part to deficient production of
Address correspondence to: P. G. Holt, to the placenta, and their release at the IL-12 (12), which is required for stabi-
Division of Cell Biology, Telethon Institute fetomaternal interface, triggered by lization of the IFN-γ transcriptional
for Child Health Research, PO Box 855, West
Perth, Western Australia 6872, Australia. antiallograft or antimicrobial respons- machinery in T cells (13), and also to
Phone: 61-8-9489-7838; Fax: 61-8-9489-7707; es, is an important cause of premature hypermethylation of the promoter of
E-mail: patrick@ichr.uwa.edu.au. termination of pregnancy (2, 3). the IFN-γ gene in neonatal CD4+ T
Conflict of interest: The author has declared In the face of these challenges to cells, which directly inhibits transcrip-
that no conflict of interest exists.
fetal survival, evolution has fashioned tion (14). Moreover, recent studies
Nonstandard abbreviations used: human
cytomegalovirus (HCMV); respiratory a range of overlapping control mech- indicate that ≥90% of circulating CD4+
syncytial virus (RSV). anisms to regulate expression of CD45RO– naive T cells in neonates are
The Journal of Clinical Investigation | June 2003 | Volume 111 | Number 11 1645