Association between Maternal Characteristics and Immune Factors TGF-ß1, TGF-ß2, and IgA in Colostrum: An Exploratory Study in Japan.

Colostrum is the first food for newborns and it contains various crucial immune factors. The concentrations of immune factors in breast milk may change depending on maternal characteristics such as body mass index, collection day, and age at first pregnancy. In this exploratory study, we investigated the association between TGF-ß1, TGF-ß2, and IgA in colostrum and rarely studied factors that affect breast milk components, including the use of labor-inducing medication, colostrum secretion, sex of newborns, breast or nipple problems, and nipple care. Breast milk samples were collected from 42 mothers and analyzed for TGF-ß1, TGF-ß2, and IgA. The results suggest that parity and mode of delivery may be correlated with the concentrations of immune factors in colostrum. However, we found no association between the immune factors in colostrum and the use of labor-inducing medications, colostrum secretion, sex of newborns, breast or nipple problems, and nipple care. These findings have some implications for further analysis of the effects of immune factors in breast milk on the prognosis of allergies in children.

Status of higher TGF-ß1 and TGF-ß2 levels in the aqueous humour of patients with diabetes and cataracts.

BACKGROUND: Transforming growth factor (TGF) is a cytokine that acts on the proliferation, migration, differentiation, and apoptosis of cells and the accumulation of extracellular matrix components. Very few studies have precisely evaluated the concentration of TGF-ß in the aqueous humour (AH) of diabetic and cataract (DMC) eyes due to the low expression of proteins in the AH or other reasons. The concentrations of TGF-ß1, -ß2, and -ß3 in the AH of the DMC group were compared with those of the age-related cataract (ARC) group. METHODS: We collected AH and lens epithelium samples from 33 DMC patients and 36 ARC patients. Luminex liquid suspension chip detection was applied to detect the concentration of TGF-ß1, -ß2, and -ß3 in the AH samples. The expression of TGFB1/2/3 in lens epithelium samples was determined by quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: The concentrations of TGF-ß1 and TGF-ß2 in AH samples of DMC eyes were higher than those of ARC eyes. The differences in TGF-ß1 and TGF-ß2 between the two groups were statistically significant (P value = 0.001 for TGF-ß1, P value = 0.023 for TGF-ß2). The difference of the correlation between TGF-ß1 and glycosylated haemoglobin was significant (P value = 0.011, and Pearson correlation coefficient = 0.306). The difference of the correlation between TGF-ß2 and glycosylated haemoglobin was significant (P value = 0.026, and Pearson correlation coefficient = 0.269). The mRNA expression levels of TGFB1 and TGFB2 were upregulated in DMC epithelium samples compared with ARC epithelium samples. The differences in TGFB1 and TGFB2 between the two groups were statistically significant (P value for TGFB1 = 0.041, P value for TGFB2 = 0.021). CONCLUSIONS: The concentrations of TGF-ß1 and TGF-ß2 in AH samples were significantly higher in DMC eyes than in ARC eyes. The higher the glycosylated haemoglobin was, the higher the concentrations of TGF-ß1 and -ß2 were. The mRNA expression of TGFB1 and TGFB2 was significantly upregulated in DMC epithelial samples compared with ARC epithelial samples, suggesting the proinflammatory status of the anterior chamber of DMC eyes.

Effects of Pre/Probiotic Supplementation on Breast Milk Levels of TGF-b1, TGF-b2, and IgA: A Systematic Review and Meta-Analysis of Randomized-Controlled Trial.

Background: Previous studies have proposed that the maternal intake of pre/probiotics may affect the immune composition of breast milk. Nevertheless, the available findings are contradictory. This meta-analysis aimed to examine the impact of maternal supplementation with pre/probiotics on the levels of total immunoglobulin A (IgA), secretory IgA (SIgA), transforming growth factor beta 1 (TGF-ß1), and TGF-2 in breast milk. Methods: PubMed and Scopus were systematically searched using a comprehensive search strategy for eligible randomized-controlled trials published up to February 2021. A random-effects model was applied to pool weighted mean difference and 95% confidence interval (CI) as effect size. Cochran's Q statistic and the I2 statistic were used to measure the between-study variance. Egger's regression test was used to assess publication bias. Results: A total of 12 different studies, with a total sample size of 1722 individuals (probiotic group: 858, placebo group: 864), were included in this meta-analysis. In the overall analysis, compared with placebo, maternal supplementation with pre/probiotics had no significant effect on concentrations of total IgA, SIgA, TGF-ß1, and TGF-ß2 in the breast milk. In the subgroup analysis, pre/probiotics did not affect total IgA, TGF-ß1, and TGF-ß2 in both colostrum/transitional and mature milk. However, a significant increase in SIgA was found in colostrum/transitional milk following pre/probiotic administration (WMD = 19.33, 95% CI: 0.83-37.83; p = 0.04), without evidence for remarkable heterogeneity (I2 = 0.0, p = 0.57). Conclusions: Maternal supplementation with pre/probiotics may increase SIgA in colostrum/transitional milk, without any effect on total IgA, TGF-ß1, and TGF-ß2.

Soluble HLA-G and TGF-ß in couples attending assisted reproduction - A possible role of TGF-ß isoforms in semen?

Soluble isoforms of the non-classical Human Leukocyte Antigen (HLA)-G as well as Transforming Growth Factor (TGF)-ß is expressed in seminal plasma possibly influencing the pregnancy potential. We wanted to examine the association of seminal plasma sHLA-G, TGF-ß1, TGF-ß2 and TGFß3 with pregnancy success in a cohort of 127 couples and 4 single women attending fertility treatment with the use of assisted reproduction technologies (ART). Soluble HLA-G, TGF-ß1, TGF-ß2 and TGF-ß3 in seminal plasma did not fluctuate significantly over time. We did not find any impact of seminal plasma sHLA-G, TGF-ß1, TGF-ß2 and TGF-ß3 on time-to-pregnancy measured as number of treatment cycles. There was a significant association between concentrations of seminal plasma sHLA-G and HLA-G variations in the 3'untranslated region (3'UTR) of the HLA-G gene, supporting and extending previous findings. Furthermore, by comparing seminal plasma concentrations of sHLA-G, TGF-ß1, TGF-ß2 and TGF-ß3 in male subjects with reduced semen quality, male subjects with normal semen quality, and sperm donors, we found that TGF-ß2 was significantly lower, and TGF-ß3 was significantly higher, in seminal plasma from sperm donors. These findings suggest that TGF-ß isoforms may influence semen quality and fertility.

Expression of transforming growth factor ß and matrix metalloproteinases in the aqueous humor of patients with congenital ectopia lentis.

It is well known that transforming growth factor ß (TGFß), which is able to stimulate multiple intracellular signaling pathways, exerts an important role in Marfan syndrome, although the effects of TGFß on congenital ectopia lentis (CEL) have yet to be fully elucidated. In the present study, the expression levels of TGFß and matrix metalloproteinases (MMPs) were investigated in the aqueous humor of patients with ectopic lentis who differed in terms of the severity of the disease. A total of 17 CEL patients with 21 eyes (aged 12.76±9.37 years) and 12 congenital cataract (CC) patients with 17 eyes (aged 6.82±9.18 years) were randomized in the present study. The levels of active TGFß and MMPs in the aqueous humor were analyzed with Luminex xMAP® technology by using commercially available Bio­Plex Pro™ Human MMP and TGFß assays. The distance from the lens edge to the pupil edge and the white to white corneal diameter (i.e. the horizontal distance between the borders of the corneal limbus) were measured, and the ratio was calculated as the degree of lens dislocation. The association between TGFß and MMP levels and the degree of lens dislocation was analyzed using Spearman's correlation test. Compared with the patients with CC, the level of TGFß2 in the patients with CEL was increased significantly. Specifically, the level of TGFß2 in the CEL patients was 855.19 pg/ml (744.33, 1,009.24), whereas it was 557.08 (438.24, 692.71) pg/ml in the CC patients (P<0.001). In addition, it was noted that the levels of MMP­2 and ­10 in the aqueous humor of the patients with CEL were higher compared with those in the CC patients, although this increase did not reach the level of statistical significance. Notably, the levels of MMP­8 and ­9 in the aqueous humor of patients with CEL were significantly lower compared with those in the CC patients (P=0.014 and P=0.002, respectively). Furthermore, a marginal correlation was identified between the severity of ectopic lentis and the levels of TGFß2 in the aqueous humor (r2=0.379; P=0.003) of the patients with CEL. Taken together, these results demonstrated that a significant correlation existed between high levels of aqueous humor TGFß2 and the severity of ectopia lentis in patients with CEL. In addition, aqueous humor TGFß2 levels in the CEL patients were significantly higher compared with those in CC patients.

Effect of HTST and Holder Pasteurization on the Concentration of Immunoglobulins, Growth Factors, and Hormones in Donor Human Milk.

Donor human milk (DHM) is submitted to Holder pasteurization (HoP) to ensure its microbiological safety in human milk banks but this treatment affects some of its bioactive compounds. The objective of this work was to compare the effects of HoP and high temperature short time (HTST) treatments on some bioactive compounds found in DHM. A total of 24 DHM batches were processed in a continuous HTST system (70, 72, and 75°C for 5-25 s) and by HoP (62.5°C for 30 min). The concentrations of immunoglobulins (Igs) A, G, and M, transforming growth factor-beta 2 (TGF-ß2), adiponectine, ghrelin, and leptin were measured using a multiplex system, whereas the concentration of epidermal growth factor (EGF) was determined by ELISA. In relation to Igs, IgG showed the highest preservation rates (87-101%) after HTST treatments, followed by IgA (54-88%) and IgM (25-73%). Ig retention after any of the HTST treatments was higher than after HoP (p < 0.001). Treatment times required to reduce the concentration of IgM by 90% (D-value) were 130, 88, and 49 s at 70, 72, and 75°C, while the number of degrees Celsius required to change the D-value by one factor of 10 (z-value) was 11.79°C. None of the heat treatments had a significant effect on the concentrations of TGF-ß2, EGF, adiponectin, and ghrelin. In contrast, leptin was detected only in 4 of the samples submitted to HoP, whereas it was present in all samples after the different HTST treatments, with retention rates ranging between 34 and 68%. Globally, the concentration of IgA, IgG, IgM, and leptin in DHM was significantly higher after HTST pasteurization performed in a continuous system designed to be used in human milk banks than after the HoP procedure that is routinely applied at present.

Functional Implications of Cross-Linked Actin Networks in Trabecular Meshwork Cells.

BACKGROUND/AIMS: The Trabecular meshwork (TM) is the tissue responsible for outflow resistance and therefore intraocular pressure. TM cells contain a contractile apparatus that is composed of actin stress fibres which run parallel to the axis of the cell and are responsible for facilitating contraction. Cross-Linked Actin Networks (CLANs) are polygonal arrangements of actin that form a geodesic network found predominantly in TM cells both in situ and in vitro. The aim of this work is to determine the functional significance of CLANs in TM cells and to assess the effect of mechanical stretch stimulation on the induction (or not) of CLANs. METHODS: We used collagen gel contraction models to demonstrate functional impairment of cells when induced to express CLANs in situ. Cyclic mechanical stretch was used to stimulate cells and measure CLANs Results: CLANs inhibited contraction and cyclic mechanical stretch induced CLANs. Furthermore, we also demonstrated that using shape alone we could predict the appearance of CLANs using a simple light microscopy technique. CONCLUSION: Taken together we have now shown, for the first time, a functional deficit In TM cells with CLANs Furthermore that shape alone can predict the appearance of CLAN containing cells. CLANs can now be linked to a functional effect and may underlie the appearance of CLANs with the pathology of primary open angle glaucoma (POAG).

Immune Components in Human Milk Are Associated with Early Infant Immunological Health Outcomes: A Prospective Three-Country Analysis.

The role of breastfeeding in improving allergy outcomes in early childhood is still unclear. Evidence suggests that immune mediators in human milk (HM) play a critical role in infant immune maturation as well as protection against atopy/allergy development. We investigated relationships between levels of immune mediators in colostrum and mature milk and infant outcomes in the first year of life. In a large prospective study of 398 pregnant/lactating women in the United Kingdom, Russia and Italy, colostrum and mature human milk (HM) samples were analysed for immune active molecules. Statistical analyses used models adjusting for the site of collection, colostrum collection time, parity and maternal atopic status. Preliminary univariate analysis showed detectable interleukin (IL) 2 and IL13 in HM to be associated with less eczema. This finding was further confirmed in multivariate analysis, with detectable HM IL13 showing protective effect OR 0.18 (95% CI 0.04-0.92). In contrast, a higher risk of eczema was associated with higher HM concentrations of transforming growth factor ß (TGFß) 2 OR 1.04 (95% CI 1.01-1.06) per ng/mL. Parental-reported food allergy was reported less often when IL13 was detectable in colostrum OR 0.10 (95% CI 0.01-0.83). HM hepatocyte growth factor (HGF) was protective for common cold incidence at 12 months OR 0.19 (95% CI 0.04-0.92) per ng/mL. Data from this study suggests that differences in the individual immune composition of HM may have an influence on early life infant health outcomes. Increased TGFß2 levels in HM are associated with a higher incidence of reported eczema, with detectable IL13 in colostrum showing protective effects for food allergy and sensitization. HGF shows some protective effect on common cold incidence at one year of age. Future studies should be focused on maternal genotype, human milk microbiome and diet influence on human milk immune composition and both short- and long-term health outcomes in the infant.

Temporal Changes of Protein Composition in Breast Milk of Chinese Urban Mothers and Impact of Caesarean Section Delivery.

Human breast milk (BM) protein composition may be impacted by lactation stage or factors related to geographical location. The present study aimed at assessing the temporal changes of BM major proteins over lactation stages and the impact of mode of delivery on immune factors, in a large cohort of urban mothers in China. 450 BM samples, collected in three Chinese cities, covering 8 months of lactation were analyzed for α-lactalbumin, lactoferrin, serum albumin, total caseins, immunoglobulins (IgA, IgM and IgG) and transforming growth factor (TGF) ß1 and ß2 content by microfluidic chip- or ELISA-based quantitative methods. Concentrations and changes over lactation were aligned with previous reports. α-lactalbumin, lactoferrin, IgA, IgM and TGF-ß1 contents followed similar variations characterized by highest concentrations in early lactation that rapidly decreased before remaining stable up to end of lactation. TGF-ß2 content displayed same early dynamics before increasing again. Total caseins followed a different pattern, showing initial increase before decreasing back to starting values. Serum albumin and IgG levels appeared stable throughout lactation. In conclusion, BM content in major proteins of urban mothers in China was comparable with previous studies carried out in other parts of the world and C-section delivery had only very limited impact on BM immune factors.

Levels of innate immune factors in preterm and term mothers' breast milk during the 1st month postpartum.

There is a paucity of data on the effect of preterm birth on the immunological composition of breast milk throughout the different stages of lactation. We aimed to characterise the effects of preterm birth on the levels of immune factors in milk during the 1st month postpartum, to determine whether preterm milk is deficient in antimicrobial factors. Colostrum (days 2-5 postpartum), transitional milk (days 8-12) and mature milk (days 26-30) were collected from mothers of extremely preterm (<28 weeks of gestation, n 15), very preterm (28-<32 weeks of gestation, n 15), moderately preterm (32-<37 weeks of gestation, n 15) and term infants (37-41 weeks of gestation, n 15). Total protein, lactoferrin, secretory IgA, soluble CD14 receptor (sCD14), transforming growth factor-ß2 (TGF-ß2), α defensin 5 (HD5), ß defensins 1 (HBD1) and 2, IL-6, IL-10, IL-13, interferon-γ, TNF-α and lysozyme (LZ) were quantified in milk. We examined the effects of lactation stage, gestational age, volume of milk expressed, mode of delivery, parity and maternal infection on milk immune factor concentrations using repeated-measures regression analysis. The concentrations of all factors except LZ and HD5 decreased over the 1st month postpartum. Extremely preterm mothers had significantly higher concentrations of HBD1 and TGF-ß2 in colostrum than term mothers did. After controlling for other variables in regression analyses, preterm birth was associated with higher concentrations of HBD1, LZ and sCD14 in milk samples. In conclusion, preterm breast milk contains significantly higher concentrations of some immune proteins than term breast milk.

A biomimetic Schlemm's canal inner wall: A model to study outflow physiology, glaucoma pathology and high-throughput drug screening.

Glaucoma is a disease that damages the optic nerve, frequently leading to blindness. Elevated intraocular pressure (IOP) is the only modifiable risk factor for glaucoma, which is expected to affect 80 million people by 2020, causing bilateral blindness in over 10 million individuals. Because pathological changes to Schlemm's canal (SC) may account for significant resistance to outflow, there is considerable interest in characterizing and evaluating the Schlemm's canal as a target for glaucoma therapeutics. In conventional, two-dimensional culture, human Schlemm's canal (HSC) cells lose spatial, mechanical and biochemical cues, resulting in altered gene expression and cell signaling than observed in vivo, compromising the clinical relevance of data obtained from such systems. Here, we report, for the first time, that 3D culture of HSC cells on microfabricated scaffolds with defined physical and biochemical cues, rescued expression of key HSC markers, VE-cadherin and PECAM1, and mediated pore formation, crucial for the Schlemm's canal regulation of IOP. We demonstrated that following treatment with the glaucopathogenic agent, TGF-ß2, HSC cells undergo an endothelial-mesenchymal transition, which together with the increase in extracellular matrix (ECM) proteins might account for the decrease in outflow facility observed in patients with high TGF-ß2 levels in their aqueous humor. We also demonstrated that unlike 2D cultures, 3D cultures of HSC cells are amenable to gene transfer. Thus, our data imply that 3D culture of HSC cells may be used as a platform to advance our understanding of HSC physiology and pathology and as a model for high-throughput drug and gene screening.

Role of TGF-ß Signaling in Remodeling of Noncoronary Artery Aneurysms in Kawasaki Disease.

Coronary artery aneurysms (CAA) remain an important complication of Kawasaki disease (KD), the most common form of pediatric acquired heart disease in developed countries. Potentially life-threatening CAA develop in 25% of untreated children and 5% of children treated with high-dose intravenous immunoglobulin during the acute phase of the self-limited vasculitis. Noncoronary artery aneurysms (NCAA) in extraparenchymal, muscular arteries occur in a minority of patients with KD who also have CAA, yet little is understood about their formation and remodeling. We postulated that activation of the transforming growth factor-ß (TGF-ß) pathway in KD may influence formation and remodeling of aneurysms in iliac, femoral, and axillary arteries, the most common sites for NCAA. We studied a resected axillary artery from one adult and endarterectomy tissue from the femoral artery from a second adult, both with a history of CAA and NCAA following KD in infancy. Histology of the axillary artery aneurysm revealed destruction of the internal elastic lamina and recanalization of organized thrombus, while the endarterectomy specimen showed dense calcification and luminal myofibroblastic proliferation. Immunohistochemistry for molecules in the TGF-ß signaling pathway revealed increased expression of TGF-ß2, TGF-ß receptor 2, and phosphorylated SMAD3. These findings suggest ongoing tissue remodeling of the aneurysms decades after the acute injury and demonstrate the importance of the TGF-ß signaling pathway in this process.

Transforming growth factor-ß (TGF-ß) signaling in healthy human fetal skin: a descriptive study.

BACKGROUND: TGF-ß plays an important role in growth and development but is also involved in scarring and fibrosis. Differences for this growth factor are known between scarless fetal wound healing and adult wound healing. Nonetheless, most of the data in this area are from animal studies or in vitro studies and, thus, information about the human situation is incomplete and scarce. OBJECTIVE: The aim of this study was to compare the canonical TGF-ß signaling in unwounded human fetal and adult skin. METHODS: Q-PCR, immunohistochemistry, Western Blot and Luminex assays were used to determine gene expression, protein levels and protein localization of components of this pathway in healthy skin. RESULTS: All components of the canonical TGF-ß pathway were present in unwounded fetal skin. Compared to adult skin, fetal skin had differential concentrations of the TGF-ß isoforms, had high levels of phosphorylated receptor-Smads, especially in the epidermis, and had low expression of several fibrosis-associated target genes. Further, the results indicated that the processes of receptor endocytosis might also differ between fetal and adult skin. CONCLUSION: This descriptive study showed that there are differences in gene expression, protein concentrations and protein localization for most components of the canonical TGF-ß pathway between fetal and adult skin. The findings of this study can be a starting point for further research into the role of TGF-ß signaling in scarless healing.

Expression of ALDH1 and TGFß2 in benign and malignant breast tumors and their prognostic implications.

The specific mechanism underlying the role of putative stem cell marker aldehyde dehydrogenase 1 (ALDH1) playing in development and progression of breast cancer is currently unclear. Transforming growth factor ß (TGFß) signaling pathway is reported to be activated in most cancers. Thus a study was initiated to explore possible differences and correlation of ALDH1 and TGFß2 expression in the most common malignant and benign tumors of the breast in Chinese women. Samples of 75 breast cancer tissues, 30 paracancerous normal tissues, and 39 fibroadenoma breast tissues were investigated for the expression of ALDH1 and TGFß2 using immunohistochemistry. The positive rates of ALDH1 and TGFß2 protein were 62.67% and 66.67%, respectively, in breast cancer tissues, which were significantly higher than that in normal fibroadenoma breast (P<0.05) and paracancerous tissues (P<0.01). ALDH1 and TGFß2 status were significantly associated with tumor histological grade and receptor status (P<0.05). Expression of ALDH1 was found to be positively correlative to TGFß2 in breast cancer (r = 0.33, P<0.01). Expression of both proteins remained significantly associated with reduced overall survival (OS) by univariate analysis (P<0.05). Multivariate Cox regression analysis showed that ALDH1 expression, tumor stage, and lymph node status are independent prognostic factors in invasive breast cancer patients. Thus ALDH1 and TGFß2 play important roles in the development of breast cancer. The ALDH1 phenotype is an independent predictor of poor prognosis, and TGFß2 signaling pathway activation might be involved in the pathological regulation of ALDH1 in breast cancer.

Osteoclast inhibition impairs chondrosarcoma growth and bone destruction.

Because Chondrosarcoma is resistant to available chemotherapy and radiation regimens, wide resection is the mainstay in treatment, which frequently results in high morbidity and which may not prevent local recurrence. There is a clear need for improved adjuvant treatment of this malignancy. We have observed the presence of osteoclasts in the microenvironment of chondrosarcoma in human pathological specimens. We utilized the Swarm rat chondrosarcoma (SRC) model to test the hypothesis that osteoclasts affect chondrosarcoma pathogenesis. We implanted SRC tumors in tibia of Sprague-Dawley rats and analyzed bone histologically and radiographically for bone destruction and tumor growth. At three weeks, tumors invaded local bone causing cortical disruption and trabecular resorption. Bone destruction was accompanied by increased osteoclast number and resorbed bone surface. Treatment of rats with the zoledronic acid prevented cortical destruction, inhibited trabecular resorption, and resulted in decreased tumor volume in bone. To confirm that inhibition of osteoclasts per se, and not off-target effects of drug, was responsible for the prevention of tumor growth and bone destruction, we implanted SRC into osteopetrotic rat tibia. SRC-induced bone destruction and tumor growth were impaired in osteopetrotic bone compared with control bone. The results from our animal model demonstrate that osteoclasts contribute to chondrosarcoma-mediated bone destruction and tumor growth and may represent a therapeutic target in particular chondrosarcoma patients.

Transforming growth factor-ß and inflammation in vascular (type IV) Ehlers-Danlos syndrome.

BACKGROUND: Vascular Ehlers-Danlos syndrome (VEDS) causes reduced life expectancy because of arterial dissections/rupture and hollow organ rupture. Although the causative gene, COL3A1, was identified >20 years ago, there has been limited progress in understanding the disease mechanisms or identifying treatments. METHODS AND RESULTS: We studied inflammatory and transforming growth factor-ß (TGF-ß) signaling biomarkers in plasma and from dermal fibroblasts from patients with VEDS. Analyses were done in terms of clinical disease severity, genotype-phenotype correlations, and body composition and fat deposition alterations. VEDS subjects had increased circulating TGF-ß1, TGF-ß2, monocyte chemotactic protein-1, C-reactive protein, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and leptin and decreased interleukin-8 versus controls. VEDS dermal fibroblasts secreted more TGF-ß2, whereas downstream canonical/noncanonical TGF-ß signaling was not different. Patients with COL3A1 exon skipping mutations had higher plasma intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, and VEDS probands had abnormally high plasma C-reactive protein versus affected patients identified through family members before any disease manifestations. Patients with VEDS had higher mean platelet volumes, suggesting increased platelet turnover because of ongoing vascular damage, as well as increased regional truncal adiposity. CONCLUSIONS: These findings suggest that VEDS is a systemic disease with a major inflammatory component. C-reactive protein is linked to disease state and may be a disease activity marker. No changes in downstream TGF-ß signaling and increased platelet turnover suggest that chronic vascular damage may partially explain increased plasma TGF-ß1. Finally, we found a novel role for dysregulated TGF-ß2, as well as adipocyte dysfunction, as demonstrated through reduced interleukin-8 and elevated leptin in VEDS.

TGF-ß2, a protective intestinal cytokine, is abundant in maternal human milk and human-derived fortifiers but not in donor human milk.

OBJECTIVE: This study compared cytokines (in particular transforming growth factor [TGF]-ß2) and lactoferrin in maternal human milk (MHM), human-derived milk fortifier (HDMF), and donor human milk (DHM). MATERIALS AND METHODS: MHM was randomly collected from breastfeeding mothers who had no infectious illness at the time of milk expression. HDMF and DHM were products derived from human milk processed by Holder pasteurization. MHM samples were collected at different times (early/late) and gestations (preterm/term). Lactoferrin was analyzed by western blotting, and cytokines were quantified using commercial enzyme-linked immunosorbent assays. Significance was determined using analysis of variance. RESULTS: In the 164 samples analyzed, TGF-ß2 concentrations in HDMF and preterm MHM (at all collection times) were fivefold higher than in DHM (p<0.05). Early preterm MHM had levels of interleukin (IL)-10 and IL-18, 11-fold higher than DHM (p<0.05). IL-6 in DHM was 0.3% of the content found in MHM. IL-18 was fourfold higher in early MHM versus late MHM regardless of gestational age (p<0.05). Lactoferrin concentration in DHM was 6% of that found in MHM. CONCLUSIONS: Pasteurization decreases concentrations of most cytokines and lactoferrin in DHM. TGF-ß2, a protective intestinal cytokine, has comparable concentrations in HDMF to MHM despite pasteurization.

Repeated intrauterine exposures to inflammatory stimuli attenuated transforming growth factor-ß signaling in the ovine fetal lung.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is one of the most common complications after preterm birth and is associated with intrauterine exposure to bacteria. Transforming growth factor-ß (TGFß) is implicated in the development of BPD. OBJECTIVES: We hypothesized that different and/or multiple bacterial signals could elicit divergent TGFß signaling responses in the developing lung. METHODS: Time-mated pregnant Merino ewes received an intra-amniotic injection of lipopolysaccharide (LPS) and/or Ureaplasma parvum serovar 3 (UP) at 117 days' and/or 121/122 days' gestational age (GA). Controls received an equivalent injection of saline and or media. Lambs were euthanized at 124 days' GA (term = 150 days' GA). TGFß1, TGFß2, TGFß3, TGFß receptor (R)1 and TGFßR2 protein levels, Smad2 phosphorylation and elastin deposition were evaluated in lung tissue. RESULTS: Total TGFß1 and TGFß2 decreased by 24 and 51% after combined UP+LPS exposure, whereas total TGFß1 increased by 31% after 7 days' LPS exposure but not after double exposures. Alveolar expression of TGFßR2 decreased 75% after UP, but remained unaltered after double exposures. Decreased focal elastin deposition after single LPS exposure was prevented by double exposures. CONCLUSIONS: TGFß signaling components and elastin responded differently to intrauterine LPS and UP exposure. Multiple bacterial exposures attenuated TGFß signaling and normalized elastin deposition.

Downregulated gene expression of TGF-ßs in diabetic oral wound healing.

BACKGROUND: Healing of tooth extraction sockets in poorly controlled diabetic patients is often delayed and accompanied by severe infection. The exact cellular and molecular mechanisms underlying the pathogenesis of this complication are still not fully understood. OBJECTIVES: The purpose of this study was to investigate molecular changes associated with delayed oral wound healing in diabetes. MATERIALS AND METHODS: Six to eight weeks old male type 2 diabetes and age matched control inbred mice were used and maxillary molar tooth extractions were performed. At 4 and 7 days after tooth extraction, the edentulous mucosa of the mice were harvested, and analyzed for histology and gene expression of key wound healing factors. RESULTS: In the diabetic model, histological analysis showed that epithelial tissue migration for wound closure was delayed after tooth extraction compared to the control. Quantitative real-time PCR revealed that expression of the TGF-ß1, TGF-ß2, TGF-ß3, TGFßRII and TGFßRIII genes was significantly downregulated in the diabetic model at 4 and 7 days after tooth extraction. CONCLUSION: These results suggest that delayed wound healing of oral mucosa in diabetes may be associated with decreased expression levels of these regulatory genes which play important roles in controlling epithelial wound closure.

Endocrine and inflammatory factors and endometriosis-associated infertility in assisted reproduction techniques.

PURPOSE: Our research aimed to evaluate the effect of endometriosis on folliculogenesis and pregnancy, and to assess the involvement of inflammatory factors (IL1b, PGE2, PGF2α, and TGFß2) in follicular fluid. METHODS: A total of 65 follicular fluid aspirates were collected. Concentrations of inflammatory factors (IL1b, PGE2, PGF2α, and TGFß2) and steroid hormones (E2, progesterone, FSH, and LH) within follicular fluid as well as serum E2 and LH concentrations were measured. The mRNA expression of IL1b, Ptgs2, aromatase, and PPARγ in granulosa cells was determined. The outcome of ART was monitored and recorded. RESULTS: The oocyte retrieval, rate of metaphase II oocyte, cleavage rate, effective embryo rate, and pregnancy rates of patients with endometriosis were all significantly lower than those of the control patients. In those with endometriosis, serum E2 concentrations were lower than those observed in controls. Aromatase levels in the granulosa cells of the endometriosis group were lower while concentrations of PGE2 in follicular fluid were higher than in the control group. Concentrations of PGE2, PGF2α, TGFß2, and IL1b were significantly correlated with each other. CONCLUSIONS: These results suggest that the outcomes of ART, in relation to serum E2 concentration, were adversely affected by the presence of endometriosis. Furthermore, the results supported that, among the endocrine and inflammatory factors, PGE2 within the follicular fluid impairs the number and quality of oocytes.