Protease Inhibitors and their Relation to Protease Activity in Human Milk

Lindberg, Tor; Ohlsson, Kjell; Weström, Björn

doi:10.1203/00006450-198206000-00016

Cited by 99 publications

(63 citation statements)

References 11 publications

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“…The relative abundance of sCD14 in breast milk (25.6 Ϯ 13.8 g/mL), when compared with its serum concentration (3 g/mL) (9), and its relative resistance to pepsin digestion, may allow significant amounts of the intact protein to reach the duodenum. Furthermore, the enhanced proteolytic resistance observed for both breast milk sCD14 and SIgA, in comparison to their purified forms, may be attributed to the breast milk abundance of alternate substrates for the digestive enzymes and to breast milk protease inhibitors (30). The first N-terminal half of sCD14 has been shown to contain all the active domains to trigger biologic responses against LPS (31).…”

Section: Discussionmentioning

confidence: 99%

Killing the Messenger in the Nick of Time: Persistence of Breast Milk sCD14 in the Neonatal Gastrointestinal Tract

2006

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Human breast milk contains several proteins that supplement the newborn mucosal defense system and prevent gastrointestinal illnesses. One of these recently identified breast milk proteins is soluble CD14 (sCD14). By being an important component of the lipopolysaccharide (LPS) receptor complex, it has been suggested that breast milk sCD14 could stimulate the newborn immune system and help reduce gastrointestinal Gram-negative infections. However, to deliver its potential immune benefits to the neonate, sCD14 would have to survive the passage through the gastrointestinal tract and retain its biologic activity. We analyzed the presence of breast milk sCD14 in the neonatal digestive system and found breast milk sCD14 to be absent from the stools of breast-fed infants. In vitro digestion analysis with simulated gastric and pancreatic fluids revealed that sCD14 is likely to survive the pepsin digestion but is more prone to been nicked and digested by pancreatin. These findings suggest that the presence of intact breast milk sCD14 in the upper digestive system could promote innate immunity in this low bacteria density lumen. The low concentration of sCD14 in the LPS-rich environment of the distal gastrointestinal tract (i.e. commensal microflora) could prevent excessive inflammation.

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Section: Discussionmentioning

confidence: 99%

Killing the Messenger in the Nick of Time: Persistence of Breast Milk sCD14 in the Neonatal Gastrointestinal Tract

2006

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“…The protective effect of proteins could explain some of the contradictory reported data since fasted or fed subjects were used without discrimination. The presence of protease inhibitors in human milk and bovine milk [33,114,120,121,233] could also explain this protective effect.…”

Section: Epidermal Growth Factormentioning

confidence: 99%

Growth factors from bovine milk and colostrum: composition, extraction and biological activities

Gauthier

Pouliot

Maubois

2006

Lait

125

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-EGF, BTC, IGF-I, IGF-II, TGF-β1, TGF-β2, FGF1 and 2, and PDGF are the main growth factors present in bovine milk and colostrum. All of these growth factors are also found in human milk but at a lower concentration. The various compositional data reported in the literature vary greatly but it is evidenced that the day of lactation has the most important effect. Milk growth factors are characterized by a neutral to alkaline isoelectric point (pI) and a molecular mass between 6400 g·mol -1 and 30000 g·mol -1 . However, many of the growth factors are in a latent form, bound to high-molecular-mass proteins. Milk growth factors are resistant generally to pasteurization but disulfide reducing agents have been found to inactivate some species such as TGF-β's. The published data on bioavailability of milk growth factors are somewhat contradictory but it is generally accepted that they are resistant to gastric digestion and they can exert local and systemic effects on the gastrointestinal tract. Cation-exchange chromatography has been widely used for the extraction of milk growth factors because of the basic nature of these molecules. Membrane separations such as microfiltration (MF) have also been used successfully for the extraction of immunoglobulins and of some growth factors from colostrum, while ultrafiltration (UF) was successful only at separating IGF-I and IGF-II in whey. Milk growth factor extracts have been developed for various applications such as treatment of gastrointestinal disorders and skin diseases, wound healing, and induction of oral tolerance.

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“…Also, there is no evidence of intragastric protein digestion for the first several days of age (43). Moreover, human milk contains high concentrations of antiproteases, al-antichymotrypsin and a,-antitrypsin, that impede proteolysis (44). Thus, TNF-a in human milk may persist in the recipient long enough to be biologically active.…”

Section: Subject Selection This Study Was Approved By the Institutionalmentioning

confidence: 99%

Tumor Necrosis Factor-α in Human Milk

et al. 1992

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ABSTRACT. We previously demonstrated that certain biologic activities in human milk were partially blocked by antibodies directed against human tumor necrosis factor-a (TNF-a). In this study, immunochemical methods were used to verify the presence of TNF-a in human milk obtained during the first few days of lactation. Gel filtration revealed the presence of TNF-a by RIA in molecular weight fractions between 80 and 195 kD. TNF-a could not be detected consistently by conventional Western blotting or cytotoxic assays. Although immunoreactive bands were detected by a Western blot-lZ5I protein A technique in TNF-a-positive fractions from gel filtration, those bands proved to be nonspecific. TNF-a in milk was reliably quantified by the competitive RIA. Those studies revealed that the concentrations of TNF-a in milk were 620 +. FMLP, N-formyl-I-methionyl-I-leucyl-I-phenylalanineIt is widely accepted that much of the protective effect of human milk (1) is due to a direct-acting antimicrobial system that consists of humoral and cellular components (2-6). The leukocytes are of particular interest because they include not only neutrophils and lymphocytes but also macrophages (4-6) that appear morphologically to be activated (4, 5). The results of recent studies (7) are consistent with those previous observations. In those investigations, human milk macrophages moved faster than human peripheral blood mononuclear leukocytes in a threedimensional, relatively adherence-independent assay. It was subsequently demonstrated that the increased motility of those macrophages was due in large part to either TNF-a or TNF-a- inducing factors in human milk. When blood mononuclear cells were incubated in whole human colostrum or its whey protein fraction, the motility of the blood monocytes increased to that of milk macrophages (8). The activity was abrogated by trypsin and considerably decreased by polyclonal antibodies to rhTNFa. Three peaks of chemokinetic activity, corresponding to 50-55, 25, and 10-17 kD, were demonstrated by gel filtration chromatography. The chemokinetic activity peaks in human milk were blocked by antibodies to rhTNF-a. In addition, the studies suggested that some of the limited cytotoxic activity of human milk against murine L-929 cells was blocked by antibodies to rhTNF-a (8).In view of the pleiotropic effects of TNF-cu upon the immunologic system (9-19), it was important to verify whether TNFa or TNF-a-inducing agents are present in human milk in sufficient quantities to potentially affect the recipient infant. Indeed, the presence of sufficient amounts of those agents would suggest that human milk might affect the maturation of the defense systems of the infant. We investigated this question by examining human milk for TNF-a by immunochemical methods. Furthermore, we sought to determine whether the leukocytes in human milk are a source of this cytokine by examining them for TNF-a and for its RNA. MATERIALS AND METHODS Subject selection. This study was approved by the InstitutionalReview Board for Human Resea...

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Protease Inhibitors and their Relation to Protease Activity in Human Milk

Cited by 99 publications

References 11 publications

Killing the Messenger in the Nick of Time: Persistence of Breast Milk sCD14 in the Neonatal Gastrointestinal Tract

Killing the Messenger in the Nick of Time: Persistence of Breast Milk sCD14 in the Neonatal Gastrointestinal Tract

Growth factors from bovine milk and colostrum: composition, extraction and biological activities

Tumor Necrosis Factor-α in Human Milk

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