Showing papers on "Antimicrobial peptides published in 2001"

Innate antimicrobial peptide protects the skin from invasive bacterial infection.

Abstract: In mammals, several gene families encode peptides with antibacterial activity, such as the beta-defensins and cathelicidins. These peptides are expressed on epithelial surfaces and in neutrophils, and have been proposed to provide a first line of defence against infection by acting as 'natural antibiotics'. The protective effect of antimicrobial peptides is brought into question by observations that several of these peptides are easily inactivated and have diverse cellular effects that are distinct from antimicrobial activity demonstrated in vitro. To investigate the function of a specific antimicrobial peptide in a mouse model of cutaneous infection, we applied a combined mammalian and bacterial genetic approach to the cathelicidin antimicrobial gene family. The mature human (LL-37) and mouse (CRAMP) peptides are encoded by similar genes (CAMP and Cnlp, respectively), and have similar alpha-helical structures, spectra of antimicrobial activity and tissue distribution. Here we show that cathelicidins are an important native component of innate host defence in mice and provide protection against necrotic skin infection caused by Group A Streptococcus (GAS).

Cationic peptides: effectors in innate immunity and novel antimicrobials

Abstract: Summary Cationic antimicrobial peptides are produced by all organisms, from plants and insects to human beings, as a major part of their immediately effective, nonspecific defences against infections. With the increasing development of antibiotic resistance among key bacterial pathogens, there is an urgent need to discover novel classes of antibiotics. Therefore, cationic peptides are being developed through clinical trials as anti-infective agents. In addition to their ability to kill microbes, these peptides seem to have effect or functions in innate immunity and can upregulate the expression of multiplegenes in eukaryotic cells. One such function might involve the dampening of signalling by bacterial molecules such as lipopolysaccharide and lipoteichoic acid.

NF-kappaB signaling pathways in mammalian and insect innate immunity

Abstract: Innate immunity is the first line of defense against infectious microorganisms. The innate immune system relies on germ line-encoded pattern recognition receptors (PRRs) to recognize pathogen-derived substances (Janeway 1989). Activation of the innate immune system through these receptors leads to the expression of a vast array of antimicrobial effector molecules that attack microorganisms at many different levels. The innate immune system appeared early in evolution, and the basic mechanisms of pathogen recognition and activation of the response are conserved throughout much of the animal kingdom (Hoffmann et al. 1999). In contrast to innate immunity, the adaptive immune system generates antigen-specific receptors, antibodies, and T-cell receptors by somatic cell DNA rearrangement. These receptors, found only in higher eukaryotes, recognize specific pathogen-encoded proteins. Mammals have a complex immune response, which relies on communication between the innate and adaptive arms of the immune system. The innate immune response generates a costimulatory signal, which is required in combination with antigen-specific recognition to activate T-cells and the adaptive immune system. Antigen-specific recognition in the absence of costimulation can lead to anergy rather than activation (Janeway 1989). Thus, the activation of an antigen-specific response is coupled to infection through the innate immune system. Insects have a very potent innate immune response that effectively combats a broad spectrum of pathogens. For example, Drosophila can withstand, and clear, bacterial burdens that, relative to their size, would be lethal to mammals (Hoffmann and Reichhart 1997). Induction of innate immunity in both mammals and insects leads to the activation of similar effector mechanisms, such as stimulation of cell-based phagocytic activity and expression of antimicrobial peptides (Hoffmann et al. 1999). For example, Drosophila produce a wide range of potent antimicrobial peptides in response to infection by fungi or bacteria (Hoffmann and Reichhart 1997). Induction of the antimicrobial peptides is regulated at the level of transcription, and they are expressed primarily in the fat body, the insect liver analog. Recent studies have revealed striking similarities in the signaling pathways used by humans and flies to activate their innate immune responses. In both cases, infection leads to the activation of Toll-like receptors (TLRs), which in turn initiate intracellular signaling cascades that culminate in the activation of NFB/Rel family transcription factors. In this review, we discuss recent advances in understanding the signaling pathways in mammalian and Drosophila innate immunity, with emphasis on the mechanisms by which NFB/Rel family proteins are activated.

Staphylococcus aureus resistance to human defensins and evasion of neutrophil killing via the novel virulence factor MprF is based on modification of membrane lipids with L-lysine

Abstract: Defensins, antimicrobial peptides of the innate immune system, protect human mucosal epithelia and skin against microbial infections and are produced in large amounts by neutrophils. The bacterial pathogen Staphylococcus aureus is insensitive to defensins by virtue of an unknown resistance mechanism. We describe a novel staphylococcal gene, mprF, which determines resistance to several host defense peptides such as defensins and protegrins. An mprF mutant strain was killed considerably faster by human neutrophils and exhibited attenuated virulence in mice, indicating a key role for defensin resistance in the pathogenicity of S. aureus. Analysis of membrane lipids demonstrated that the mprF mutant no longer modifies phosphatidylglycerol with l-lysine. As this unusual modification leads to a reduced negative charge of the membrane surface, MprF-mediated peptide resistance is most likely based on repulsion of the cationic peptides. Accordingly, inactivation of mprF led to increased binding of antimicrobial peptides by the bacteria. MprF has no similarity with genes of known function, but related genes were identified in the genomes of several pathogens including Mycobacterium tuberculosis, Pseudomonas aeruginosa, and Enterococcus faecalis. MprF thus constitutes a novel virulence factor, which may be of general relevance for bacterial pathogens and represents a new target for attacking multidrug resistant bacteria.

Amphipathic alpha helical antimicrobial peptides.

Abstract: Antimicrobial peptides (AMPs) that assume an amphipathic alpha helical structure are widespread in nature. Their activity depends on several parameters including the sequence, size, degree of structure formation, cationicity, hydrophobicity and amphipathicity. The analysis of numerous natural AMPs provided representative values for these parameters and led to a sequence template with which to generate potent artificial lead AMPs. Sequences were then varied in a rational manner, using both natural and nonproteinogenic amino acids, to probe the individual roles of each parameter in modulating biological activity. A high cationicity combined with a stabilized amphipathic alpha helical structure conferred enhanced cidal activity towards all the cell types considered, and was a requirement for Gram-positive bacteria and fungi. An elevated helicity also correlated with increased hemolytic activity. The structural requirements for activity against several Gram-negative bacteria were instead considerably less stringent, so that it persisted in peptides in which formation of a helical structure and/or amphipathicity were impeded. Either a reduced charge or a reduced hydrophobicity resulted in generally inactive peptides. These observations, combined with the kinetics of bacterial membrane permeabilization and time-killing are discussed in terms of currently accepted models of action for this type of peptide. The simple guidelines obtained in this study allowed the design of highly active shortened AMPs and may be generally useful in the development of this type of peptides as anti-infective agents.

Genome-wide analysis of the Drosophila immune response by using oligonucleotide microarrays.

Abstract: To identify new Drosophila genes involved in the immune response, we monitored the gene expression profile of adult flies in response to microbial infection by using high-density oligonucleotide microarrays encompassing nearly the full Drosophila genome Of 13,197 genes tested, we have characterized 230 induced and 170 repressed by microbial infection, most of which had not previously been associated with the immune response Many of these genes can be assigned to specific aspects of the immune response, including recognition, phagocytosis, coagulation, melanization, activation of NF-κB transcription factors, synthesis of antimicrobial peptides, production of reactive oxygen species, and regulation of iron metabolism Additionally, we found a large number of genes with unknown function that may be involved in control and execution of the immune response Determining the function of these genes represents an important challenge for improving our knowledge of innate immunity Complete results may be found at http://wwwfruitflyorg/expression/immunity/

Dermcidin: a novel human antibiotic peptide secreted by sweat glands.

Abstract: Antimicrobial peptides are an important component of the innate response in many species. Here we describe the isolation of the gene Dermcidin, which encodes an antimicrobial peptide that has a broad spectrum of activity and no homology to other known antimicrobial peptides. This protein was specifically and constitutively expressed in the sweat glands, secreted into the sweat and transported to the epidermal surface. In sweat, a proteolytically processed 47–amino acid peptide was generated that showed antimicrobial activity in response to a variety of pathogenic microorganisms. The activity of the peptide was maintained over a broad pH range and in high salt concentrations that resembled the conditions in human sweat. This indicated that sweat plays a role in the regulation of human skin flora through the presence of an antimicrobial peptide. This peptide may help limit infection by potential pathogens in the first few hours following bacterial colonization.

Human β-defensin 4: a novel inducible peptide with a specific salt-sensitive spectrum of antimicrobial activity

Abstract: SPECIFIC AIMSThe aim of this study was to identify and characterize a novel human member of the β-defensin family by screening genomic sequences, analyze its genomic structure, tissue distribution, and regulation, and evaluate its antimicrobial and chemoattractant activities.PRINCIPAL FINDINGS1. Analysis of the genomic and cDNA sequences of the novel β-defensinTo identify genomic sequences around human β-defensin 2 at the chromosomal region 8p23, the peptide sequence of this β-defensin was used to perform a ‘basic local alignment search tool’ (BLAST) search in the High Throughput Genomic (HTG) division of the GenBank. Accession numbers AF202031, AF252831, AF189745, and AC074340 were found and subsequently screened for the presence of the β-defensin consensus pattern. Analysis of the clone AF202031 revealed a genomic sequence coding for the carboxy-terminal region of a putative novel β-defensin, which was found in several HTG clones available at GenBank and subsequently termed hBD-4. The full-length cDNA f...

Identification of a novel, multifunctional beta-defensin (human beta-defensin 3) with specific antimicrobial activity. Its interaction with plasma membranes of Xenopus oocytes and the induction of macrophage chemoattraction.

Abstract: Previous studies have shown the implication of β-defensins in host defense of the human body. The human β-defensins 1 and 2 (hBD-1, hBD-2) have been isolated by biochemical methods. Here we report the identification of a third human β-defensin, called human β-defensin 3 (hBD-3; cDNA sequence, Genbank accession no. AF295370), based on bioinformatics and functional genomic analysis. Expression of hBD-3 is detected throughout epithelia of many organs and in non-epithelial tissues. In contrast to hBD-2, which is upregulated by microorganisms or tumor necrosis factor-α (TNF-α), hBD-3 expression is increased particularly after stimulation by interferon-γ. Synthetic hBD-3 exhibits a strong antimicrobial activity against gram-negative and gram-positive bacteria and fungi, including Burkholderia cepacia. In addition, hBD-3 activates monocytes and elicits ion channel activity in biomembranes, specifically in oocytes of Xenopus laevis. This paper also shows that screening of genomic sequences is a valuable tool with which to identify novel regulatory peptides. Human β-defensins represent a family of antimicrobial peptides differentially expressed in most tissues, regulated by specific mechanisms, and exerting physiological functions not only related to direct host defense.

Antimicrobial peptides: properties and applicability.

Abstract: All organisms need protection against microorganisms, e. g. bacteria, viruses and fungi. For many years, attention has been focused on adaptive immunity as the main antimicrobial defense system. However, the adaptive immune system, with its network of humoral and cellular responses is only found in higher animals, while innate immunity is encountered in all living creatures. The turning point in the appreciation of the innate immunity was the discovery of antimicrobial peptides in the early eighties. In general these peptides act by disrupting the structural integrity of the microbial membranes. It has become clear that membrane-active peptides and proteins play a crucial role in both the innate and the adaptive immune system as antimicrobial agents. This review is focused on the functional and structural features of the naturally occurring antimicrobial peptides, and discusses their potential as therapeutics.

Peptide antibiotics in mast cells of fish

Abstract: Antimicrobial peptides are increasingly recognized as a critical first line of defence against many pathogens and have been isolated from epithelial tissues and blood cells of many vertebrates, as well as from prokaryotes, plants and invertebrates1,2. Here we show that 'piscidins', a previously undiscovered family of peptide antibiotics isolated from fish, reside in mast cells, an immune cell of uncertain function that is present in all vertebrate classes3,4. Until now, no peptide antibiotic has been isolated from the mast cells of any animal, and our discovery indicates that these cells may be critical in fighting many infectious diseases.

Evaluation of the effects of peptide antibiotics human β-defensins-1/-2 and LL-37 on histamine release and prostaglandin D2 production from mast cells

Abstract: Antimicrobial peptides, human beta-defensins (hBD-1/-2), and LL-37 (a peptide of human cathelicidin CAP18) are predominately expressed at epithelial tissues, where they participate in the innate host defense by killing invading microorganisms. In this study, to investigate the interactions between epithelial cell-derived antimicrobial peptides and mast cells, we evaluated the effects of hBD-1/-2 and LL-37 on mast cell functions using rat peritoneal mast cells. hBD-2 and LL-37 but not hBD-1 induced histamine release and intracellular Ca(2+) mobilization, and hBD-2 was more potent than LL-37. Interestingly, histamine release and intracellular Ca(2+) mobilization elicited by hBD-2 and LL-37 were markedly suppressed by BAPTA-AM (an intracellular Ca(2+) chelating agent), pertussis toxin and U-73122 (a phospholipase C inhibitor). In addition, among the peptides examined, only hBD-2 significantly induced PGD(2) production, which was abolished by indomethacin (cyclooxygenase-1/-2 inhibitor) but not NS-398 (cyclooxygenase-2 inhibitor), suggesting that hBD-2-induced PGD(2) production is mediated by cyclooxygenase-1. Likewise, the PGD(2) production was suppressed by pertussis toxin and U-73122. These observations suggest that hBD-2 and LL-37 stimulate mast cells to mobilize intracellular Ca(2+) and release histamine or generate PGD(2) in a G protein-phospholipase C-dependent manner. Thus, hBD-2 and LL-37 may have modulatory effects on inflammatory reactions.

De novo design, synthesis, and characterization of antimicrobial beta-peptides.

Abstract: β-Peptides are a class of polyamides that have been demonstrated to adopt a variety of helical conformations. Recently, a series of amphiphilic L+2 helical β-peptides were designed, which were intended to mimic the overall physicochemical properties of a class of membrane-active antimicrobial peptides, including magainin and cecropin. Although these peptides showed potent antimicrobial activity, they also showed significant activity against human erythrocytes. Operating under the assumption that their lack of specificity arose from excessive hydrophobicity, two additional β-peptides H-(β3-HAla-β3-HLys-β3-HVal)n-NH2 (n = 4, 5) were designed and synthesized. Both have high antimicrobial activities, but very low hemolytic potencies. The peptides bind in an L+2 conformation to phospholipid vesicles, inducing leakage of entrapped small molecules. The peptides have a low affinity for membranes consisting of neutral phosphatidylcholine lipids, but bind avidly to vesicles containing 10 mol % of acidic phosphatidy...

Mediators of Innate Immunity That Target Immature, But Not Mature, Dendritic Cells Induce Antitumor Immunity When Genetically Fused with Nonimmunogenic Tumor Antigens

Abstract: Chemokine receptors are differentially expressed on immature and mature dendritic cells (DC). Herein, we demonstrate for the first time that murine antimicrobial peptides β-defensins 2 and 3 bind murine CCR6, similarly to inflammatory chemokine macrophage-inflammatory protein 3α, and they chemoattract bone marrow-derived immature, but not mature DC. Using various chemokines or defensins fused with nonimmunogenic tumor Ags, we studied their capacity to delivery Ags to subsets of immune cells to elicit antitumor immunity. We demonstrate that DNA immunizations with fusion constructs with β-defensin 2 or inflammatory chemokines that target immature DC, but not homeostatic chemokines secondary lymphoid tissue chemokine, CCL21, or stromal cell-derived factor 1, CXCL12, which chemoattract mature DC, elicit humoral, protective, and therapeutic immunity against two different syngeneic lymphomas.

Antimicrobial mechanisms of fish phagocytes and their role in host defense

Abstract: Phagocytosis is a primitive defense mechanism in all multicellular animals. Phagocytes such as macrophages and neutrophils play an important role in limiting the dissemination of infectious agents, and are responsible for the eventual destruction of phagocytosed pathogens. These cells have evolved elaborate killing mechanisms for destroying pathogens. In addition to their repertoire of degradative enzymes and antimicrobial peptides, macrophages and neutrophils can be activated to produce a number of highly toxic molecules. Production of reactive oxygen and nitrogen intermediates by these cells are potent cytotoxic mechanisms against bacteria and protozoan pathogens. Studies in fish suggest that the biological basis of these inducible killing mechanisms is similar to those described in mammals. More recent work suggest novel roles for regulating these killing responses in fish. In this review, we describe the biological basis of these killing mechanisms and how they are regulated in fish.

Localized antimicrobial peptide expression in human gingiva.

Abstract: The stratified epithelia of the oral cavity are continually exposed to bacterial challenge that is initially resisted by innate epithelial factors and by the recruitment of neutrophils. Antimicrobial peptides from phagocytes and epithelia contribute to this antimicrobial barrier. Using antibodies and in situ hybridization, we explored antimicrobial peptide expression in the varied epithelia of the periodontium and in cultured gingival epithelial cells. In gingival tissue, mRNA for the beta-defensins, human beta-defensin 1 (hBD-1) and human beta-defensin 2 (hBD-2) was predominately localized in suprabasal stratified epithelium and the peptides were detected in upper epithelial layers consistent with the formation of the stratified epithelial barrier. In cultured epithelial cells, both hBD-1 and -2 peptides were detected only in differentiating, involucrin-positive epithelial cells, although hBD-2 required stimulation by proinflammatory mediators or bacterial products for expression. Beta-defensins were not detected in junctional epithelium (JE) that serves as the attachment to the tooth surface. In contrast, alpha-defensins and cathelicidin family member LL-37 were detected in polymorphonuclear neutrophils (PMNs) that migrate through the JE, a localization that persists during inflammation, when the JE and surrounding tissue are highly infiltrated with PMNs. Thus, the undifferentiated JE contains exogenously expressed alpha-defensins and LL-37, and the stratified epithelium contains endogenously expressed beta-defensins. These findings show that defensins and other antimicrobial peptides are localized in specific sites in the gingiva, are synthesized in different cell types, and are likely to serve different roles in various regions of the periodontium.

Synergistic Interactions between Mammalian Antimicrobial Defense Peptides

Abstract: A single animal can express several cationic antimicrobial peptides with different sequences and structures. We demonstrate that mammalian peptides from different structural classes frequently show synergy with each other and selectively show synergy with human lysozyme.

The role of mammalian antimicrobial peptides and proteins in awakening of innate host defenses and adaptive immunity.

Abstract: Since we live in a dirty environment, we have developed many host defenses to contend with microorganisms. The epithelial lining of our skin, gastrointestinal tract and bronchial tree produces a number of antibacterial peptides, and our phagocytic neutrophils rapidly ingest and enzymatically degrade invading organisms, as well as produce peptides and enzymes with antimicrobial activities. Some of these antimicrobial moieties also appear to alert host cells involved in both innate host defense and adaptive immune responses. The epithelial cells are a source of constitutively produced beta defensin (HBD1) and proinflammatory cytokine-inducible beta defensins (HBD2 and -3) and cathelicidin (LL37). The neutrophils-derived antimicrobial peptides are released on demand from their cytoplasmic granules. They include the enzymes cathepsin G and chymase, azurocidin, a defensins and cathelicidin. In contrast, C5a and C3b are produced by activation of the serum complement cascade. The antimicrobial moieties direct the migration and activate target cells by interacting with selected G-protein-coupled seven-transmembrane receptors (GPCRs) on cell surfaces. The beta defensins interact with the CCR6 chemokine GPCRs, whereas cathelicidins interact with the low-affinity FPRL-1 receptors. The neutrophil-derived cathepsin G acts on the high-affinity FMLP receptor (GPCR) known as FPR, while the receptors for chymase and azurocidin have not been identified as yet. The serum-derived C5a uses a GPCR known as C5aR to mediate its chemotactic and cell-activating effects. Consequently, all these ligand-receptor interactions in addition to mediating chemotaxis also activate receptor-expressing cells to produce other mediators of inflammation.

Genetic engineering of plants to enhance resistance to fungal pathogens—a review of progress and future prospects

Abstract: Recent applications of techniques in plant molecular biology and biotechnology to the study of host–pathogen interactions have resulted in the identification and cloning of numerous genes involved in the defense responses of plants following pathogen infection. These include: genes that express proteins, peptides, or antimicrobial compounds that are directly toxic to pathogens or that reduce their growth in situ; gene products that directly inhibit pathogen virulence products or enhance plant structural defense genes, that directly or indirectly activate general plant defense responses; and resistance genes involved in the hypersensitive response and in the interactions with avirulence factors. The introduction and expression of these genes, as well as of antimicrobial genes from nonplant sources, in a range of transgenic plant species have shown that the development of fungal pathogens can be significantly reduced. The extent of disease reduction varies with the strategy employed as well as with the char...

The antibacterial arm of the Drosophila innate immune response requires an IκB kinase

Abstract: In both mammals and Drosophila, microbial infection activates Toll-like receptor (TLR) signaling pathways as a part of the innate host defense response (for review, see Anderson 2000). TLR-mediated signaling pathways are essential for appropriate responses to bacterial infection. In addition, mouse Tlr4 mediates septic shock associated with infection by gram-negative bacteria (Vogel 1992; Poltorak et al. 1998). The available data indicate that different microbial cell wall components activate different Toll-like receptor signaling pathways, which regulate distinct sets of target genes. In mammals, TLR4 is the prime mediator of responses to bacterial lipopolysaccharide, while TLR2 mediates responses to bacterial peptidoglycans (Poltorak et al. 1998; Takeuchi et al. 1999; for review, see Beutler 2000). The best-studied aspect of the Drosophila innate immune response is the rapid transcriptional induction of antimicrobial peptide genes in response to infection (Hultmark 1993; Hoffmann 1995). Infection by different classes of microorganisms leads to the preferential induction of particular subsets of antimicrobial peptides (Lemaitre et al. 1997), indicating that different microbial components activate different signaling pathways. At least two Toll-related signaling pathways are required for the activation of the Drosophila antimicrobial peptide genes. The Toll pathway itself, which was first identified because of its essential role in Drosophila embryonic patterning (Anderson et al. 1985), is essential for the induction of an antifungal peptide gene, drosomycin, although the antibacterial peptide genes are still induced in Toll pathway mutants (Lemaitre et al. 1996). Another Drosophila member of the Toll family, 18-wheeler, is required for the normal induction of attacin, an antibacterial peptide gene, but mutations in 18-wheeler do not prevent the induction of other antibacterial peptides (Williams et al. 1997). The imd gene is important for the induction of Diptericin and other antibacterial peptides (Lemaitre et al. 1995a; Corbo and Levine 1996) and, therefore, appears to be a component of a third signaling pathway activated by infection, but its biochemical function is not known. Each of the three Drosophila signaling pathways activated by infection leads to activation of NF-κB/Rel dimers, just as the mammalian TLRs activate NF-κB. All three Drosophila Rel proteins, Dorsal, Dif, and Relish, are expressed in the fat body cells that produce the antimicrobial peptides, and all three are activated within 30 min after infection by translocation from the cytoplasm to the nuclei (Ip at al. 1993; Lemaitre et al. 1995b; Stoven et al. 2000). Adults that lack Dif fail to induce Drosomycin, an antifungal peptide, and Defensin, which is active against gram-positive bacteria, but the other antimicrobial peptide genes are induced normally (Manfruelli et al. 1999; Meng et al. 1999; Rutschmann et al. 2000). Animals that lack Dorsal show normal induction of the antimicrobial peptide genes in response to infection (Lemaitre et al. 1995b), although Dorsal may act redundantly with Dif in larvae (Manfruelli et al. 1999; Rutschmann et al. 2000). Relish is a compound protein with an N-terminal Rel domain and a C-terminal IκB-like domain, similar to mammalian p100 and p105 (Dushay et al. 1996). Relish is activated by signal-dependent proteolysis, which liberates the N-terminal Rel domain, allowing it to translocate into nuclei (Stoven et al. 2000). Adults that lack Relish completely fail to induce the antibacterial peptides Diptericin and Cecropin and show reduced induction of the other antimicrobial peptides (Hedengren et al. 1999). The signaling pathway that activates Relish and controls induction of the antibacterial peptide genes has not been defined. We carried out a genetic screen to identify EMS-induced mutations on the Drosophila third chromosome that affect the antibacterial signaling pathway (Wu and Anderson 1998). A large number of mutants were identified and named ird (immune response deficient) mutants. This screen identified two alleles of the ird5 gene on the basis of the failure of homozygous mutant larvae to induce a diptericin-lacZ reporter gene in response to infection. Here we show that the ird5 gene is essential for antibacterial responses and encodes a Drosophila homolog of mammalian IκB kinases.

Human Toll-like receptor 2 mediates induction of the antimicrobial peptide human beta-defensin 2 in response to bacterial lipoprotein.

Abstract: Recognition of pathogens by Drosophila Toll or human Toll-like receptors results in translocation of Dorsal or its human homologue NF-kappaB, respectively; in Drosophila, this is followed by the production of antimicrobial peptides serving as antimicrobial effector system of the innate immune response. We investigated whether human Toll-like receptors also mediate induction of the synthesis of antimicrobial peptides. We found that HEK293 cells transfected with Toll-like receptor 2, but not wild-type cells responded to stimulation with bacterial lipoprotein by production of human beta-defensin 2. Furthermore, the human lung epithelial cell line A549 was found to constitutively express Toll-like receptor 2 and to produce beta-defensin 2 in response to bacterial lipoprotein. This response was abrogated by blocking the signaling pathway activated through Toll-like receptors by transfecting the A549 cells with a dominant-negative form of IRAK-2. Thus, exposure of human cells to bacterial lipoprotein elicits production of the antimicrobial peptide beta-defensin 2 through Toll-like receptor 2.