Bioactive molecules in milk and their role in health and disease: The role of transforming growth factor-beta (original) (raw)
Related papers
Cytokines in milk and the role of TGF-beta
Best Practice & Research Clinical Endocrinology & Metabolism, 2018
Cytokines are required for normal growth and development of the mammary gland and TGF-b prominently represents an established effector of apoptosis, e.g., during involution of the mammary gland. By the control of intracellular signaling pathways, including JAK/STAT, MAPK, PI-3K, and NF-kB, cytokines efficiently regulate cell proliferation and inflammation in the breast. Therefore, cytokines are discussed also in a context of malignant mammary growth. As a group of tissue hormones produced by somatic cells or by cells from the immune system, cytokines are defined by their immunomodulatory potential. Over the past 40 years, multiple cytokines were identified in colostrum and milk. Importantly, cytokines derived from mammary secretions after birth are required for maturation of the immune system in the developing gastrointestinal tract from the suckling. Moreover, recent studies have further assessed the particular interactions between probiotic bacterial strains and cytokines. In light of the increasing prevalence of inflammatory diseases of the gastrointestinal system, the effects of probiotic microorganisms during milk fermentation may have immunotherapeutic potential in the future.
Pediatric Allergy and Immunology, 2010
Oddy WH, Rosales F. A systematic review of the importance of milk TGF-β on immunological outcomes in the infant and young child. Pediatr Allergy Immunol 2010: 21: 47–59. © 2009 Mead Johnson Nutrition Journal compilation © 2009 John Wiley & Sons A/SCytokines in milk like transforming growth factor-beta (TGF-β) have been shown to induce oral tolerance in experimental animal studies. However, human studies are less consistent with these findings. The primary objective of this review was to conduct a systematic review of published studies on the association between TGF-β identified in human milk and immunological outcomes in infancy and early childhood. Human prospective clinical studies were identified through MEDLINE, CAB Abstracts, Biological Abstracts and Scopus. Selection criteria included: well described populations of mothers and infants, time of milk sampling, immunological outcome measures and analytical methods of TGF-β determination. We considered a wide range of immunological outcomes in infancy and early childhood, such as wheeze, atopy, eczema and the immunoglobulin switch. Twelve human studies were included in the review and 67% showed a positive association with TGF-β1 or TGF-β2 demonstrating protection against allergy-related outcomes in infancy and early childhood. High variability in concentrations of TGF-β was noted between and within studies, some of it explained by maternal history of atopy or by consumption of probiotics. Human milk TGF-β appears to be essential in developing and maintaining appropriate immune responses in infants and may provide protection against adverse immunological outcomes, corroborating findings from experimental animal studies. Further large clinical studies in diverse human populations are indicated to confirm these results.
Early human …, 2004
Background: Transforming growth factor (TGF)-β has a crucial effect on IgA production, which is the major humoral effector of mucosal immunity. Breast milk contains the abundant amount of TGF-β in the early period of lactation. Aim–study design: To verify the notion that TGF-β in breast milk might contribute to the development of IgA production in newborns, we investigated the association of TGF-β in maternal colostrum with an increase of serum IgA in newborns during the first month of life. Subjects and methods: The concentrations of TGF-β1 and TGF-β2, including IL-6 and IL-10, in colostrum samples from 55 healthy mothers were determined by ELISA. The levels of IgA and IgM in serum samples collected from corresponding newborn babies at birth and at 1 month of age were measured by ELISA. Results: TGF-β1 and TGF-β2 were detected in substantial quantities in all colostrum samples, but IL-6 and IL-10 were present only in a proportion of samples. An increase of serum IgA in newborn during the first month of life was significantly higher than that of serum IgM (p<0.001). Notably, an increase of serum IgA in newborns during 1 month of life was well correlated with levels of both TGF-β1 (r=0.38, p=0.005) and TGF-β2 (r=0.45, p=0.0005) in colostrum, while that of IgM was marginally correlated with colostral TGF-β2 (r=0.28, p=0.04). The association of increase of serum IgA in newborns with IL-6 and IL-10 in colostrum was not evident. Conclusion: Our findings suggest that TGF-β in colostrum might serve as the starter of IgA production in newborn infants.
Dairy Science & Technology, 2011
The objective of the study was to characterize the effects of preheating of milk and of pasteurization steps during whey processing on the separation of transforming growth factor-beta 2 (TGF-β2) from whey protein concentrates (WPCs). Three heating conditions were applied to skimmed milk: no heating, 63°C for 20 s and 68°C for 20 s. The effect of pasteurizing liquid acid whey and liquid WPC was also assessed. Heating milk at 63 or 68°C decreased TGF-β2 content of whey. A pasteurization treatment of whey at 72°C for 15 s further decreased their TGF-β2 content. However, an additional pasteurization of WPCs significantly increased TGF-β2 only in samples from unheated milk. Acid precipitation of WPCs showed that cumulative heat treatments increased the amount of precipitate obtained, and that pH 4.5 was found to be optimal in terms of TGF-β2 content of precipitates. The highest TGF-β2 concentrations in acid precipitates (>10,000 pg.mg −1 solids) were obtained with a combination of heating milk at 63°C for 20 s and pasteurization of whey at 72°C for 15 s. It was found that, although whey obtained from raw milk represents the best source of TGF-β2, an appropriate selection of heat treatments of liquid whey and WPC improves the recovery of TGF-β2. The presence of casein and minor whey proteins in TGF-β2-enriched fractions underlines the occurrence of complex heatinduced interactions between TGF-β2 and other milk constituents. 热处理对从酸沉乳清浓缩蛋白中提取TGF-β2回收率的影响 摘要 本文研究了牛乳的预热和乳清的巴氏杀菌过程对从乳清浓缩蛋白中提取TGF-β2回收 率的影响。脱脂乳分别经过三种不同的热处理, 分别为未加热、63°C加热20s和68°C加热 20s; 同时还评定了巴氏杀菌的液态酸乳清和液态乳清浓缩蛋白中TGF-β2的回收率。脱脂乳
1998
Degradation of epidermal growth factor (EGF) in human gastric and duodenal lumen was analyzed by incubating 125 I-labeled or unlabeled human recombinant EGF with human gastric or duodenal luminal fluids in vitro. Degradation of EGF was assessed by measuring the generation of acid soluble radioactivity or by reversed-phase high-performance liquid chromatography (HPLC). Incubation with gastric luminal fluids resulted in a time-and dose-dependent degradation of labeled and unlabeled EGF at pH 2.5 but not at pH 7.5. Duodenal luminal fluids, on the other hand, degraded EGF at pH 7.5 but not at pH 2.5. The rate of degradation of unlabeled EGF in gastric luminal fluids was nearly 12-fold higher than the rate of degradation of labeled EGF, whereas only a slight difference in rates of degradation of labeled and unlabeled EGF was observed in duodenal luminal fluids. High-performance liquid chromatography analysis detected three major degradation products that eluted with retention time of 17.5 min, 20.0 min, and 22.5 min that was associated with a reduction of intact EGF (retention time 23.5 min). Defatted and decaseinated supernatant of bovine milk effectively inhibited the degradation of EGF in both gastric and duodenal luminal fluids. Dietary derived protease inhibitors, such as soya bean trypsin inhibitor, lima bean trypsin inhibitor, egg white protease inhibitor, and Bowman-Birk protease inhibitor prevented EGF degradation in duodenal luminal fluids but failed to inhibit EGF degradation in gastric luminal fluids. These results suggest that bovine milk may contain specific inhibitors that protect EGF from proteolytic degradation in human gastric lumen.
Distribution of bioactive factors in human milk samples
International Breastfeeding Journal, 2019
Background: Breast milk provides nutrition for infants and also contains a variety of bioactive factors that influence the development of the newborn. Human milk is a complex biological fluid that can be separated into different layers (water phase and lipid phase with its component water and lipid fractions). It can affect the developing human body along the whole length of the gastrointestinal tract, and through the circulation, its factors may reach every organ. Methods: In the present study, we analyzed milk samples collected monthly for 6 months from 16 mothers from the 4 th week postpartum between 2014 and 2016 in Baranya County, Hungary. The 96 samples provided us information about the fluctuation of certain bioactive factors during the first 6 months of lactation. We investigated with Luminex technology the concentrations of several cytokines (CD40, Flt-3L), chemokines (MCP-1, RANTES, GRO, MIP-1ß, MDC, eotaxin, fractalkine), and epidermal growth factor (EGF). Paired t-tests and one-way ANOVA followed by Bonferroni post-hoc tests were used to compare the data. Results: We detected the presence of each bioactive factor in every layer of the milk samples during the first 6 months of breastfeeding in widespread concentration ranges. In the case of GRO, MIP-1ß, MDC, Flt-3L, fractalkine, and eotaxin, the concentrations were constant during the first 6 months of lactation. The water phase of human milk contained higher factor concentrations compared to both fractions of the lipid phase for most factors (except eotaxin and MIP-1ß). The concentrations of CD40, EGF, MCP-1, and RANTES in the first 3 months were significantly different compared to the values detected between 4 th and 6 th months. In the water phase, the level of MCP-1 was significantly decreased, while all of the other factors increased during the 4 th through 6 th months. We found significantly higher EGF, GRO, and RANTES levels in the water fraction compared to the lipid fraction of the lipid phase. Conclusions: The novel findings of this investigation were the presence of Flt-3L and MDC in all layers of breast milk, and nearly all bioactive factors in the lipid phase. Due to their widespread physiological effects these factors may have an essential role in organogenesis.
Biological activity of bovine milk
Livestock Production Science, 2001
The mitogenic activity of milk from different stages of lactation was studied in primary cultures of undifferentiated bovine mammary epithelial cells. The mitogenic activity, measured as DNA synthesis, was 3-4-fold higher in colostrum than in basal medium. The mitogenic activity declined rapidly after calving, and in mid and late lactation the effect was inhibitory, not stimulatory. The content of IGF-I in milk varied with stage of lactation declining from more than 300 ng per ml in colostrum to 1-2 ng per ml in mid lactation and increasing to 20 ng per ml in late lactation. The difference in mitogenic activities between colostrum and mature milk was closely related to the difference in IGF-I content. The changes in IGF-I, however, cannot account for the inhibitory effect of mid and late lactation milk and the difference in the mitogenic effect of colostrum and BPMS (bovine prepartum milk-like secretion). The amounts of IGF binding proteins (24, 28,(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44) in milk followed the same pattern as IGF-I with high content in early lactation and low content in mid lactation. The discrepancies between mitogenic activity and IGF-I content may in some, but not all, cases be related to the content of binding proteins.
Isolation and characterization of epidermal growth factor from human milk
FEBS Letters, 1985
Epidermal growth factor (EGF) has been purified from human milk. The purification was monitored with a human placental membrane radioreceptor assay using murine salivary epidermal growth factor I (mEGF I) as a competitive ligand and was achieved exclusively by the use of reverse-phase liquid chromatography (RPLC). The sequential use of preparative, semipreparative and analytical RPLC on an octylsilica support with solvent systems of different solute selectivity such as pyridine formate, triethylammonnium phosphate or perfluorocarbonic acids in the presence of n-propanol or acetonitrile allowed purification to homogeneity with 5 consecutive runs. The molecular mass, amino acid composition and NH,-terminal sequence of human EGF were determined. Gas-phase microsequencing of residues 1-17 revealed the following sequence: Asn-Ser-Asp-Ser-Glu-X-Pro-Leu-Ser-His-Asp-Gly-Tyr-X-Leu-X-Asp which is identical with the NH,-terminof urogastrone from human urine. The purified polypeptide competes with mEGF for the placental membrane receptor with a k, of 1 ng. Furthermore, it stimulates the anchorage-dependent as well as-independent proliferation of human and rat indicator cells with half-maximal stimulation at 1 and 2.5 ng/ml, respectively. Although human epidermal growth factor has been unequivocally identified in human milk and-for the first time-shown to be identical with urogastrone from human urine, the high-resolution techniques employed have also revealed the presence of EGF-related molecules which await further characterization. It is possible that EGF and the EGF-related growth factors possess important regulatory functions in normal growth of the human breast during pregnancy and lactation as well as in abnormal growth during mammary tumor formation and progression.
American Journal of Physiology-Gastrointestinal and Liver Physiology, 2013
Human milk contains substantial amounts of transforming growth factor (TGF)-β, particularly the isoform TGF-β2. We previously showed in preclinical models that enterally administered TGF-β2 can protect against necrotizing enterocolitis (NEC), an inflammatory bowel necrosis of premature infants. In this study we hypothesized that premature infants remain at higher risk of NEC than full-term infants, even when they receive their own mother's milk, because preterm human milk contains less bioactive TGF-β than full-term milk. Our objective was to compare TGF-β bioactivity in preterm vs. full-term milk and identify factors that activate milk-borne TGF-β. Mothers who delivered between 23 0/7 and 31 6/7 wk or at ≥37 wk of gestation provided milk samples at serial time points. TGF-β bioactivity and NF-κB signaling were measured using specific reporter cells and in murine intestinal tissue explants. TGF-β1, TGF-β2, TGF-β3, and various TGF-β activators were measured by real-time PCR, enzy...