Effect of anti-inflammatory agents on transforming growth factor beta over-expressing mouse brains: a model revised

Background  

The over-expression of transforming growth factor β-1(TGF-β1) has been reported to cause hydrocephalus, glia activation, and vascular amyloidβ (Aβ) deposition in mouse brains. Since these phenomena partially mimic the cerebral amyloid angiopathy (CAA) concomitant to Alzheimer's disease, the findings in TGF-β1 over-expressing mice prompted the hypothesis that CAA could be caused or enhanced by the abnormal production of TGF-β1. This idea was in accordance with the view that chronic inflammation contributes to Alzheimer's disease, and drew attention to the therapeutic potential of anti-inflammatory drugs for the treatment of Aβ-elicited CAA. We thus studied the effect of anti-inflammatory drug administration in TGF-β1-induced pathology.     

Role of TGF-β1 haplotypes in the occurrence of myocardial infarction in young Italian patients

Background  

Transforming growth factor beta 1 (TGF-β1) gene play an important role in the acute myocardial infarction (AMI), however no investigation has been conducted so far in young AMI patients.     

Transforming growth factor-β1 induces matrix metalloproteinase-9 and cell migration in astrocytes: roles of ROS-dependent ERK- and JNK-NF-κB pathways

Background  

Transforming growth factor-β (TGF-β) and matrix metalloproteinases (MMPs) are the multifunctional factors during diverse physiological and pathological processes including development, wound healing, proliferation, and cancer metastasis. Both TGF-β and MMPs have been shown to play crucial roles in brain pathological changes. Thus, we investigated the molecular mechanisms underlying TGF-β1-induced MMP-9 expression in brain astrocytes.     

Erratum to: Early administration of propofol protects against endotoxin-induced acute lung injury in rats by inhibiting the TGF-β1-Smad2 dependent pathway

Objective  

To assess the effects of propofol treatments at different time points on acute lung injury and on the expression of transforming growth factor (TGF)-β1 and the downstream target of TGF-β1, Smad 2, in the lung tissues in the endotoxic rats.     

The influence of physical exercise on the generation of TGF-β1, PDGF-AA,and VEGF-A in adipose tissue

Adipose tissue is an important organ that produces and secretes hormones and cytokines, including TGF-β1, PDGF-AA, and VEGF-A. The goal of the present study was to investigate the influence of a single session of acute exercise, as well as the prolonged endurance training on the production of TGF-β1, PDGF-AA, and VEGF-A in the subcutaneous white adipose tissue in rats. Rats were randomly divided into two groups: untrained (UT, n = 30) and trained rats (T, subjected to 6-week endurance training with increasing load, n = 29). Both groups were subjected to an acute exercise session with the same work load. The rats were killed before (UTpre, Tpre), immediately after (UT0h, T0h), or 3 h (UT3h, T3h) after exercise and adipose tissue samples collected. Growth factor mRNA was evaluated using RT-PCR; the protein levels were measured before and after training (UTpre and Tpre) using the immunoenzymatic method. TGF-β1 and PDGF-AA mRNA levels were decreased in the UT3h rats compared to the UTpre rats (P = 0.0001 and P = 0.03, respectively), but the VEGF-A mRNA level remained unchanged in the UT0h and UT3h rats compared to UTpre rats. TGF-β1, PDGF-AA and VEGF-A mRNA levels were decreased in the T3h rats compared to Tpre (P = 0.0002, P = 0.02, and P = 0.03, respectively). TGF-β1, PDGF-AA and VEGF-A mRNA levels significantly increased in the Tpre rats compared to UTpre (all P = 0.0002). However, the protein levels remained constant. In conclusion, prolonged physical exercise increases growth factor mRNA in adipose tissue but not protein levels.     

TGF-β1 blockade of microglial chemotaxis toward Aβ aggregates involves SMAD signaling and down-regulation of CCL5

Background  

Overactivated microglia that cluster at neuritic plaques constantly release neurotoxins, which actively contribute to progressive neurodegeneration in Alzheimer's disease (AD). Therefore, attenuating microglial clustering can reduce focal neuroinflammation at neuritic plaques. Previously, we identified CCL5 and CCL2 as prominent chemokines that mediate the chemotaxis of microglia toward beta-amyloid (Aβ)aggregates. Although transforming growth factor-β1 (TGF-β1) has been shown to down-regulate the expression of chemokines in activated microglia, whether TGF-β1 can reduce the chemotaxis of microglia toward neuritic plaques in AD remains unclear.     

Anti-fibrotic effect of thalidomide through inhibiting TGF-β-induced ERK1/2 pathways in bleomycin-induced lung fibrosis in mice

Objectives  

This study is designed to confirm the anti-fibrotic effect of thalidomide on bleomycin-induced lung fibrosis in a mouse model and to identify whether this anti-fibrotic effect is associated with inhibition of the transforming growth factor-β (TGF-β)-induced extracellular signal-regulated kinase1/2 (ERK1/2).     

Effects of transforming growth factor-beta (TGF-β1) on satellite cell activation and survival during oxidative stress

The regulation of adult skeletal muscle repair and regeneration is largely due to the contribution of resident adult myogenic precursor cells called satellite cells. The events preceding their participation in muscle repair include activation (exit from quiescence), proliferation, and differentiation. This study examined the effects of transforming growth factor-beta (TGF-β1) on satellite cell activation, determined whether TGF-β1 could maintain quiescence in the presence of hepatocyte growth factor (HGF), and whether the regulation of satellite cell activation with TGF-β1 improves the ability of satellite cells to withstand oxidative stress. The addition of TGF-β1 during early satellite cell activation (0–48 h) or during the proliferative phase (48–96 h) maintained and induced satellite cell quiescence, respectively, as determined by myogenic differentiation (MyoD) protein expression. TGF-β1 also attenuated satellite cell activation when used with HGF. Finally, the role of quiescence in protecting cells against oxidative stress was examined. TGF-β1 treatment and the low pH satellite cell preparation procedure, a technique that forestalls spontaneous activation in vitro, both enhanced survival of cultured satellite cells following hydrogen peroxide treatment. These findings indicate that TGF-β1 is capable of maintaining and inducing satellite cell quiescence and suggest methods to maintain satellite cell quiescence may improve their transplantation efficiency.     

Resistance to Exogenous TGF-β Effects in Patients with Systemic Lupus Erythematosus

Background  

The mechanisms underlying the loss of self-tolerance in systemic lupus erythematosus (SLE) are incompletely deciphered. TGF-β plays a key role in self-tolerance demonstrated by the onset of a fatal autoimmune syndrome associated with lupus autoantibodies in mice lacking a functional TGF-β receptor. The present work aims to define whether resistance to TGF-β might contribute to the pathogenesis of SLE.     

The Response of Bone Marrow-Derived Mesenchymal Stem Cells to Dynamic Compression Following TGF-β3 Induced Chondrogenic Differentiation

The objective of this study was to investigate the hypothesis that the application of dynamic compression following transforming growth factor-β3 (TGF-β3) induced differentiation will further enhance chondrogenesis of mesenchymal stem cells (MSCs). Porcine MSCs were encapsulated in agarose hydrogels and cultured in a chemically defined medium with TGF-β3 (10 ng/mL). Dynamic compression (1 Hz, 10% strain, 1 h/day) was initiated at either day 0 or day 21 and continued until day 42 of culture; with TGF-β3 withdrawn from some groups at day 21. Biochemical and mechanical properties of the MSC-seeded constructs were evaluated up to day 42. The application of dynamic compression from day 0 inhibited chondrogenesis of MSCs. This inhibition of chondrogenesis in response to dynamic compression was not observed if MSC-seeded constructs first underwent 21 days of chondrogenic differentiation in the presence of TGF-β3. Spatial differences in sGAG accumulation in response to both TGF-β3 stimulation and dynamic compression were observed within the constructs. sGAG release from the engineered construct into the surrounding culture media was also dependent on TGF-β3 stimulation, but was not effected by dynamic compression. Continued supplementation with TGF-β3 appeared to be a more potent chondrogenic stimulus than the application of 1 h of daily dynamic compression following cytokine initiated differentiation. In the context of cartilage tissue engineering, the results of this study suggest that MSC seeded constructs should be first allowed to undergo chondrogenesis in vitro prior to implantation in a load bearing environment.     

Transient Supplementation of Anabolic Growth Factors Rapidly Stimulates Matrix Synthesis in Engineered Cartilage

The purpose of the presented work is to examine the response of engineered cartilage to a transient, 2-week application of anabolic growth factors compared to continuous exposure in in vitro culture. Immature bovine chondrocytes were suspended in agarose hydrogel and cultured for 28 days (Study 1) or 42 days (Study 2) in chondrogenic media with TGF-β1, TGF-β3, or IGF-I either added for only the first 14 days in culture or added to the media for the entire study period. In both studies, there were no statistical differences in tissue mechanical or biochemical properties between the growth factors on day 14. In Study 1, growth factor removal led to a significant and drastic increase in Young’s modulus and glycosaminoglycans content compared to continuously exposed controls on day 28. In Study 2, both TGF-β1 and β3 led to significantly higher mechanical properties and collagen content vs. IGF-I on day 42. These results indicate that the rapid rise in tissue properties (previously observed with TGF-β3 only) is not dependent on the type but rather the temporal application of the anabolic growth factor. These findings shed light on possible techniques to rapidly develop engineered cartilage tissue for the future treatment of osteoarthritis.     

Cyclic mechanical stretching modulates secretion pattern of growth factors in human tendon fibroblasts

The objective of the study was to investigate whether the response profile of the growth factor of human tendon fibroblasts could be beneficially influenced through the application of mechanical stretch. It was considered that this would elucidate structural and functional problems, often seen after tendon and ligament healing. The secretion pattern of transforming growth factor-beta (TGF-β), platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) was determined in mechanically stretched fibroblasts and compared to non-stretched controls. Human tendon fibroblasts were experimentally stretched for 15 and 60 min at a frequency of 1 Hz and an amplitude of 5%. The secretion of TGF-β, PDGF and bFGF was measured by enzyme-linked immuno-sorbent assay. All the growth factors investigated were indeed secreted by human tendon fibroblasts both in stretched cells and controls. Mechanical stretch increased the secretion pattern of the growth factors. The increased concentrations of TGF-β, bFGF and PDGF after cyclical mechanical stretching may have a positive influence on tendon and ligament healing through stimulation of cell proliferation, differentiation and matrix formation. Electronic Publication     

Role of TGF-β in the Induction of Foxp3 Expression and T Regulatory Cell Function

Introduction  A number of studies have suggested that transforming growth factor beta (TGF-β) plays a critical role in immune suppression mediated by Foxp3⁺ regulatory T cells. TGF-β in concert with interleukin 2 is a potent induction factor for the differentiation of Foxp3⁺ Treg from naive precursors. Polyclonal TGF-β-induced Treg (iTreg) are capable of preventing the autoimmune syndrome that develops in scurfy mice that lack Foxp3⁺ Treg. Antigen-specific iTreg can be used to both prevent and treat autoimmune gastritis that is induced by transfer of naive or primed autoantigen-specific T cells. TGF-β complexed with latency-associated peptide is expressed on the surface of activated thymus-derived Treg. Coculture of activated Treg with naive responder T cells results in the de novo generation of fully functional Foxp3⁺ T cells in a contact-dependent and TGF-β-dependent manner. Conclusions and Speculations  Generation of functional Foxp3⁺ T cells via this pathway may represent a mechanism by which Treg maintain tolerance and expand their repertoire.     

Soluble vascular endothelial growth factor (VEGF) receptor-1 inhibits migration of human monocytic THP-1 cells in response to VEGF

Objective  

We aimed to investigate the regulation and contribution of vascular endothelial growth factor (VEGF) and sFlt-1(1–3) to human monocytic THP-1 migration.     

TGF-β and Regulatory T Cell in Immunity and Autoimmunity

Introduction  The immune response is controlled by several inhibitory mechanisms. These mechanisms include regulatory T cells, which exist in multiple classes. Notable among these are Foxp3-expressing regulatory T cells (Treg), NKT cells, and Tr1 cells. Common to these mechanisms are inhibitory cytokines such as interleukin-10 and transforming growth factor-beta (TGF-β). TGF-β and Foxp3-expressing Treg cells are critical in maintaining self-tolerance and immune homeostasis. Discussions  The immune suppressive functions of TGF-β and Treg cells are widely acknowledged and extensively studied. Nonetheless, recent studies revealed the positive roles for TGF-β and Treg cells in shaping the immune system and the inflammatory responses. In this paper, we will discuss the role of these mechanisms in the control of immunity and autoimmunity and the mechanisms that underlie how these molecules control these responses.     

TGFβ signaling in the brain increases with aging and signals to astrocytes and innate immune cells in the weeks after stroke

Background  

TGFβ is both neuroprotective and a key immune system modulator and is likely to be an important target for future stroke therapy. The precise function of increased TGF-β1 after stroke is unknown and its pleiotropic nature means that it may convey a neuroprotective signal, orchestrate glial scarring or function as an important immune system regulator. We therefore investigated the time course and cell-specificity of TGFβ signaling after stroke, and whether its signaling pattern is altered by gender and aging.