Identification of defensin binding to C1 complement

Panyutich, Alexander V.; Szold, Oded; Poon, Pak H.; Tseng, Yiou; Ganz, Tomas

doi:10.1016/0014-5793(94)01261-x

Cited by 56 publications

(27 citation statements)

References 24 publications

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“…Defensins have been shown to bind to ␣ 2 -macroglobulin (30), serpins (31), and C1q (32). Despite the formation of these complexes, the plasma concentration of defensins is only 50 ng/ml in healthy subjects (33) and thus very low in comparison with the levels of defensins in neutrophils.…”

Section: Discussionmentioning

confidence: 97%

The Human Antibacterial Cathelicidin, hCAP-18, Is Bound to Lipoproteins in Plasma

Sørensen¹,

Bratt²,

Johnsen

et al. 1999

Journal of Biological Chemistry

103

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Cathelicidins are a family of antibacterial and lipopolysaccharide-binding proteins. hCAP-18, the only human cathelicidin, is a major protein of the specific granules of human neutrophils. The plasma level of hCAP-18 is >20-fold higher than that of other specific granule proteins relative to their levels within circulating neutrophils. The aim of this study was to elucidate the background for this high plasma level of hCAP-18. Plasma was subjected to molecular sieve chromatography, and hCAP-18 was found in distinct high molecular mass fractions that coeluted with apolipoproteins A-I and B, respectively. The association of hCAP-18 with lipoproteins was validated by the cofractionation of hCAP-18 with lipoproteins using two different methods for isolation of lipoproteins from plasma. Furthermore, the level of hCAP-18 in delipidated plasma was <1% of that in normal plasma. Immunoprecipitation of very low, low, and high density lipoprotein particles with anti-apolipoprotein antibodies resulted in coprecipitation of hCAP-18. hCAP-18 belongs to the cathelicidins, a group of antimicrobial peptides found in mammalian neutrophils (1). The cathelicidins share a highly conserved N-terminal prosequence that is homologous to cathelin, a protein first isolated from porcine leukocytes (2). The active antimicrobial domains of the cathelicidins generally reside in their C termini. The antimicrobial activity is observed only when the C-terminal domain is cleaved from the holoprotein (3-5). The C termini of the cathelicidins show great variability in amino acid sequence, but they are all highly cationic and hydrophobic. The antimicrobial part of many cathelicidins, including the C terminus of hCAP-18 (also named LL-37), has been shown to bind lipopolysaccharide (6).Porcine and bovine neutrophils contain a variety of cathelicidins, whereas hCAP-18 is the only cathelicidin identified in humans (6 -8). hCAP-18 is a major protein of the specific granules of human neutrophils (9), but is also present in squamous epithelia (10) and in keratinocytes during inflammatory skin diseases (11). Transcripts for hCAP-18 have been found in lung tissue by in situ hybridization (12).We have previously shown that the relative plasma levels of specific granule proteins from neutrophils are very low compared with the levels in circulating neutrophils (Ͻ1%) (13). In contrast, the concentration of hCAP-18 in plasma is ϳ1.2 g/ ml, which is Ͼ20% of the amount present in circulating neutrophils (14). In general, neutrophils are activated to release their granule proteins only when present outside the circulation. Thus, degranulation is unlikely to be the cause of this high plasma level of hCAP-18 since other granule proteins localized in the same granule subset would be expected to have equally high plasma levels as hCAP-18. This is not the case. Thus, a specific mechanism must exist to sequester hCAP-18 in the circulation and provide the relatively high concentration of this pro-bactericidal protein in plasma. Since hCAP-18 partitions mainly in the hydrop...

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Section: Discussionmentioning

confidence: 97%

The Human Antibacterial Cathelicidin, hCAP-18, Is Bound to Lipoproteins in Plasma

Sørensen¹,

Bratt²,

Johnsen

et al. 1999

Journal of Biological Chemistry

103

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“…For example, it has been shown that human ␣-defensins, HNP 1-3, are bound by activated ␣ 2 -macroglobulin (29), and by several other serum proteins, including C1q, ␣ 1 -proteinase inhibitor, ␣ 1 -antichymotrypsin, ␣ 2 -antiplasmin, and antithrombin III (30,31). It remains to be determined whether these defensins bind to glycan moieties, or whether any of the proteins also bind -defensins.…”

Section: Discussionmentioning

confidence: 99%

Activity of α- and θ-Defensins against Primary Isolates of HIV-1

Wang

Owen

Rudolph

et al. 2004

The Journal of Immunology

181

149

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θ-Defensins are lectin-like, cyclic octadecapeptides found in the leukocytes of nonhuman primates. They are also homologues of the more familiar α-defensins expressed by humans and certain other mammals. This study compares the ability of six θ-defensins (hominid retrocyclins 1–3 and rhesus θ-defensins 1–3) and four human α-defensins (human neutrophil peptides (HNPs) 1–4) to bind gp120 and CD4. In addition, we compared the ability of these θ-defensins and HNP-1 to protect J53-BL cells (an indicator cell line) from primary HIV-1 isolates that varied in subtype and coreceptor usage. The most potent θ-defensin, retrocyclin-2, bound with exceptionally high affinity to gp120 (KD, 9.4 nM) and CD4 (KD, 6.87 nM), and its effectiveness against subtype B isolates (IC50, 1.05 ± 0.28 μg/ml; 520 ± 139 nM) was approximately twice as great as that of HNP-1 on a molar basis. We also show, for the first time, that human α-defensins, HNPs 1–3, are lectins that bind with relatively high affinity to gp120 (KD range, 15.8–52.8 nM) and CD4 (KD range, 8.0–34.9 nM). Proteins found in human and FBS bound exogenous HNP-2 and retrocyclin-1, and competed with their ability to bind gp120. However, even the low concentrations of α-defensins found in normal human serum suffice to bind over half of the gp120 spikes on HIV-1 and a higher percentage of cell surface CD4 molecules. Although this report principally concerns the relationship between carbohydrate-binding and the antiviral properties of α- and θ-defensins, the lectin-like behavior of defensins may contribute to many other activities of these multifunctional peptides.

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“…Human α-and β-defensins are inactivated by serum components and higher NaCl concentrations [86,87], which also is the case for porcine pBD-1 [105]. However, protegrins maintain their activities in the presence of cations, serum or at physiological NaCl concentrations in vitro [52].…”

Section: Synergistic Interactions Among Porcine Ampsmentioning

confidence: 99%

Porcine antimicrobial peptides: New prospects for ancient molecules of host defense

Zhang¹,

Ross²,

Blecha³

2000

Vet. Res.

109

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-Antimicrobial peptides (AMPs) are small, endogenous, polycationic molecules that constitute a ubiquitous and significant component of innate immunity. These natural antibiotics have broad microbicidal activity against various bacteria, fungi, and enveloped viruses. Because most AMPs kill bacteria by physical disruption of cell membranes, which may prevent microorganisms from developing resistance against these agents, they are being explored as possible alternatives to conventional antibiotics. Pigs, like many other mammals, produce an impressive array of AMPs, which are synthesized predominantly by host leukocytic phagocytes or mucosal epithelial cells. Currently, more than a dozen distinct porcine AMPs have been identified and a majority belongs to the cathelicidin family. This review briefly summarizes recent advances in porcine AMP research with an emphasis on the diverse biological functions of each peptide. Mechanisms of action of these AMPs and their role in the resistance to infections are considered. Finally, the current status of pharmaceutical and agricultural uses of AMPs as well as future prospects for their application in the food animal industry is discussed.pig / antimicrobial peptide / cathelicidin / defensin / innate immunity Résumé -Peptides antimicrobiens porcins : nouvelles perspectives pour d'anciennes molécules de défense de l'hôte. Les peptides antimicrobiens sont de petites molécules endogènes, polycationiques, qui représentent un élément important et ubiquitaire des défenses immunes naturelles. Ces antibiotiques naturels ont un effet antimicrobien à large spectre, à la fois contre des bactéries, des moisissures et des virus enveloppés. Comme la plupart de ces peptides antimicrobiens tuent les bactéries par altération physique de leur membrane, ce qui peut éviter le développement de souches microbiennes résistantes à ces agents, ils représentent des alternatives possibles à l'emploi des antibiotiques classiques. Le porc, comme de nombreux autres mammifères, produit une gamme importante de peptides antimicrobiens, synthétisés pour l'essentiel par les leucocytes à activité phagocytaire, ou par les cellules épithéliales des muqueuses. Il y a actuellement plus d'une douzaine de peptides antimicrobiens identifiés chez le porc, dont la majorité fait partie de la famille des cathélicidines. Cet article résume les progrès récents accomplis dans le domaine des peptides antimicrobiens du porc, Vet. Res. 31 (2000) 277-296 277

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Identification of defensin binding to C1 complement

Cited by 56 publications

References 24 publications

The Human Antibacterial Cathelicidin, hCAP-18, Is Bound to Lipoproteins in Plasma

The Human Antibacterial Cathelicidin, hCAP-18, Is Bound to Lipoproteins in Plasma

Activity of α- and θ-Defensins against Primary Isolates of HIV-1

Porcine antimicrobial peptides: New prospects for ancient molecules of host defense

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