Transforming growth factor beta

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Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other signaling proteins. Transforming growth factor beta_sentence_0

TGFB proteins are produced by all white blood cell lineages. Transforming growth factor beta_sentence_1

Activated TGF-β complexes with other factors to form a serine/threonine kinase complex that binds to TGF-β receptors. Transforming growth factor beta_sentence_2

TGF-β receptors are composed of both type 1 and type 2 receptor subunits. Transforming growth factor beta_sentence_3

After the binding of TGF-β, the type 2 receptor kinase phosphorylates and activates the type 1 receptor kinase that activates a signaling cascade. Transforming growth factor beta_sentence_4

This leads to the activation of different downstream substrates and regulatory proteins, inducing transcription of different target genes that function in differentiation, chemotaxis, proliferation, and activation of many immune cells. Transforming growth factor beta_sentence_5

TGF-β is secreted by many cell types, including macrophages, in a latent form in which it is complexed with two other polypeptides, latent TGF-beta binding protein (LTBP) and latency-associated peptide (LAP). Transforming growth factor beta_sentence_6

Serum proteinases such as plasmin catalyze the release of active TGF-β from the complex. Transforming growth factor beta_sentence_7

This often occurs on the surface of macrophages where the latent TGF-β complex is bound to CD36 via its ligand, thrombospondin-1 (TSP-1). Transforming growth factor beta_sentence_8

Inflammatory stimuli that activate macrophages enhance the release of active TGF-β by promoting the activation of plasmin. Transforming growth factor beta_sentence_9

Macrophages can also endocytose IgG-bound latent TGF-β complexes that are secreted by plasma cells and then release active TGF-β into the extracellular fluid. Transforming growth factor beta_sentence_10

Among its key functions is regulation of inflammatory processes, particularly in the gut. Transforming growth factor beta_sentence_11

TGF-β also plays a crucial role in stem cell differentiation as well as T-cell regulation and differentiation. Transforming growth factor beta_sentence_12

Because of its role in immune and stem cell regulation and differentiation, it is a highly researched cytokine in the fields of cancer, auto-immune diseases, and infectious disease. Transforming growth factor beta_sentence_13

The TGF-β superfamily includes endogenous growth inhibiting proteins; an increase in expression of TGF-β often correlates with the malignancy of many cancers and a defect in the cellular growth inhibition response to TGF-β. Transforming growth factor beta_sentence_14

Its immunosuppressive functions then come to dominate, contributing to oncogenesis. Transforming growth factor beta_sentence_15

The dysregulation of its immunosuppressive functions is also implicated in the pathogenesis of autoimmune diseases, although their effect is mediated by the environment of other cytokines present. Transforming growth factor beta_sentence_16

Structure Transforming growth factor beta_section_0

The primary 3 mammalian types are: Transforming growth factor beta_sentence_17

Transforming growth factor beta_unordered_list_0

  • TGF beta 1 – TGFB1Transforming growth factor beta_item_0_0
  • TGF beta 2 – TGFB2Transforming growth factor beta_item_0_1
  • TGF beta 3 – TGFB3Transforming growth factor beta_item_0_2

A fourth member, TGF beta 4, has been identified in birds – TGRB4 (synonyms: endometrial bleeding associated factor beta-4 (EBAF), Lefty preproprotein, LEFTA; Left-Right Determination Factor 2; LEFTYA; Left-Right Determination Factor A; Transforming Growth Factor Beta-4; Protein Lefty-2; Protein Lefty-A). Transforming growth factor beta_sentence_18

A fourth member of the subfamily, TGFB4, has been identified in birds and a fifth, TGFB5, only in frogs. Transforming growth factor beta_sentence_19

The peptide structures of the TGF-β isoforms are highly similar (homologies on the order of 70–80%). Transforming growth factor beta_sentence_20

They are all encoded as large protein precursors; TGF-β1 contains 390 amino acids and TGF-β2 and TGF-β3 each contain 412 amino acids. Transforming growth factor beta_sentence_21

They each have an N-terminal signal peptide of 20–30 amino acids that they require for secretion from a cell, a pro-region called latency associated peptide (LAP - Alias: Pro-TGF beta 1, LAP/TGF beta 1), and a 112-114 amino acid C-terminal region that becomes the mature TGF-β molecule following its release from the pro-region by proteolytic cleavage. Transforming growth factor beta_sentence_22

The mature TGF-β protein dimerizes to produce a 25 KDa active protein with many conserved structural motifs. Transforming growth factor beta_sentence_23

TGF-β has nine cysteine residues that are conserved among its family. Transforming growth factor beta_sentence_24

Eight form disulfide bonds within the protein to create a cysteine knot structure characteristic of the TGF-β superfamily. Transforming growth factor beta_sentence_25

The ninth cysteine forms a disulfide bond with the ninth cysteine of another TGF-β protein to produce a dimer. Transforming growth factor beta_sentence_26

Many other conserved residues in TGF-β are thought to form secondary structure through hydrophobic interactions. Transforming growth factor beta_sentence_27

The region between the fifth and sixth conserved cysteines houses the most divergent area of TGF-β proteins that is exposed at the surface of the protein and is implicated in receptor binding and specificity of TGF-β. Transforming growth factor beta_sentence_28

Latent TGF-β complex Transforming growth factor beta_section_1

All three TGF-βs are synthesized as precursor molecules containing a propeptide region in addition to the TGF-β homodimer. Transforming growth factor beta_sentence_29

After it is synthesized, the TGF-β homodimer interacts with a Latency Associated Peptide (LAP), a protein derived from the N-terminal region of the TGF-β gene product, forming a complex called Small Latent Complex (SLC). Transforming growth factor beta_sentence_30

This complex remains in the cell until it is bound by another protein called Latent TGF-β-Binding Protein (LTBP), forming a larger complex called Large Latent Complex (LLC). Transforming growth factor beta_sentence_31

It is this LLC that gets secreted to the extracellular matrix (ECM). Transforming growth factor beta_sentence_32

In most cases, before the LLC is secreted, the TGF-β precursor is cleaved from the propeptide but remains attached to it by noncovalent bonds. Transforming growth factor beta_sentence_33

After its secretion, it remains in the extracellular matrix as an inactivated complex containing both the LTBP and the LAP which need to be further processed in order to release active TGF-β. Transforming growth factor beta_sentence_34

The attachment of TGF-β to the LTBP is by disulfide bond which allows it to remain inactive by preventing it from binding to its receptors. Transforming growth factor beta_sentence_35

Because different cellular mechanisms require distinct levels of TGF-β signaling, the inactive complex of this cytokine gives opportunity for a proper mediation of TGF-β signaling. Transforming growth factor beta_sentence_36

There are four different LTBP isoforms known, LTBP-1, LTBP-2, LTBP-3 and LTBP-4. Transforming growth factor beta_sentence_37

Mutation or alteration of LAP or LTBP can result in improper TGF-β signaling. Transforming growth factor beta_sentence_38

Mice lacking LTBP-3 or LTBP-4 demonstrate phenotypes consistent to phenotypes seen in mice with altered TGF-β signaling. Transforming growth factor beta_sentence_39

Furthermore, specific LTBP isoforms have a propensity to associate with specific LAP TGF-β isoforms. Transforming growth factor beta_sentence_40

For example, LTBP-4 is reported to bind only to TGF-β1, thus, mutation in LTBP-4 can lead to TGF-β associated complications which are specific to tissues that predominantly involves TGF-β1. Transforming growth factor beta_sentence_41

Moreover, the structural differences within the LAP's provide different latent TGF-β complexes which are selective but to specific stimuli generated by specific activators. Transforming growth factor beta_sentence_42

Activation Transforming growth factor beta_section_2

Although TGF-β is important in regulating crucial cellular activities, only a few TGF-β activating pathways are currently known, and the full mechanism behind the suggested activation pathways is not yet well understood. Transforming growth factor beta_sentence_43

Some of the known activating pathways are cell or tissue specific, while some are seen in multiple cell types and tissues. Transforming growth factor beta_sentence_44

Proteases, integrins, pH, and reactive oxygen species are just few of the currently known factors that can activate TGF-β, as discussed below. Transforming growth factor beta_sentence_45

It is well known that perturbations of these activating factors can lead to unregulated TGF-β signaling levels that may cause several complications including inflammation, autoimmune disorders, fibrosis, cancer and cataracts. Transforming growth factor beta_sentence_46

In most cases, an activated TGF-β ligand will initiate the TGF-β signaling cascade as long as TGF-β receptors I and II are available for binding. Transforming growth factor beta_sentence_47

This is due to a high affinity between TGF-β and its receptors, suggesting why the TGF-β signaling recruits a latency system to mediate its signaling. Transforming growth factor beta_sentence_48

Integrin-independent activation Transforming growth factor beta_section_3

Activation by protease and metalloprotease Transforming growth factor beta_section_4

Plasmin and a number of matrix metalloproteinases (MMP) play a key role in promoting tumor invasion and tissue remodeling by inducing proteolysis of several ECM components. Transforming growth factor beta_sentence_49

The TGF-β activation process involves the release of the LLC from the matrix, followed by further proteolysis of the LAP to release TGF-β to its receptors. Transforming growth factor beta_sentence_50

MMP-9 and MMP-2 are known to cleave latent TGF-β. Transforming growth factor beta_sentence_51

The LAP complex contains a protease-sensitive hinge region which can be the potential target for this liberation of TGF-β. Transforming growth factor beta_sentence_52

Despite the fact that MMPs have been proven to play a key role in activating TGF-β, mice with mutations in MMP-9 and MMP-2 genes can still activate TGF-β and do not show any TGF-β deficiency phenotypes, this may reflect redundancy among the activating enzymes suggesting that other unknown proteases might be involved. Transforming growth factor beta_sentence_53

Activation by pH Transforming growth factor beta_section_5

Acidic conditions can denature the LAP. Transforming growth factor beta_sentence_54

Treatment of the medium with extremes of pH (1.5 or 12) resulted in significant activation of TGF-β as shown by radio-receptor assays, while mild acid treatment (pH 4.5) yielded only 20-30% of the activation achieved by pH 1.5. Transforming growth factor beta_sentence_55

Activation by reactive oxygen species (ROS) Transforming growth factor beta_section_6

The structure of LAP is important in maintaining its function. Transforming growth factor beta_sentence_56

Structure modification of LAP can lead to disturb the interaction between LAP and TGF-β and thus activating it. Transforming growth factor beta_sentence_57

Factors that may cause such modification may include hydroxyl radicals from reactive oxygen species (ROS). Transforming growth factor beta_sentence_58

TGF-β was rapidly activated after in vivo radiation exposure ROS. Transforming growth factor beta_sentence_59

Activation by thrombospondin-1 Transforming growth factor beta_section_7

Thrombospondin-1 (TSP-1) is a matricellular glycoprotein found in plasma of healthy patients with levels in the range of 50–250 ng/ml. Transforming growth factor beta_sentence_60

TSP-1 levels are known to increase in response to injury and during development. Transforming growth factor beta_sentence_61

TSP-1 activates latent TGF-beta by forming direct interactions with the latent TGF-β complex and induces a conformational rearrangement preventing it from binding to the matured TGF-β. Transforming growth factor beta_sentence_62

Activation by Alpha(V) containing integrins Transforming growth factor beta_section_8

The general theme of integrins participating in latent TGF-β1 activation arose from studies that examined mutations/knockouts of β6 integrin, αV integrin, β8 integrin and in LAP. Transforming growth factor beta_sentence_63

These mutations produced phenotypes that were similar to phenotypes seen in TGF-β1 knockout mice. Transforming growth factor beta_sentence_64

Currently there are two proposed models of how αV containing integrins can activate latent TGF-β1; the first proposed model is by inducing conformational change to the latent TGF-β1 complex and hence releasing the active TGF-β1 and the second model is by a protease-dependent mechanism. Transforming growth factor beta_sentence_65

Conformation change mechanism pathway (without proteolysis) Transforming growth factor beta_section_9

αVβ6 integrin was the first integrin to be identified as TGF-β1 activator. Transforming growth factor beta_sentence_66

LAPs contain an RGD motif which is recognized by vast majority of αV containing integrins, and αVβ6 integrin can activate TGF-β1 by binding to the RGD motif present in LAP-β1 and LAP-β 3. Transforming growth factor beta_sentence_67

Upon binding, it induces adhesion-mediated cell forces that are translated into biochemical signals which can lead to liberation/activation of TGFb from its latent complex. Transforming growth factor beta_sentence_68

This pathway has been demonstrated for activation of TGF-β in epithelial cells and does not associate MMPs. Transforming growth factor beta_sentence_69

Integrin protease-dependent activation mechanism Transforming growth factor beta_section_10

Because MMP-2 and MMP-9 can activate TGF-β through proteolytic degradation of the latent TGF beta complex, αV containing integrins activate TGF-β1 by creating a close connection between the latent TGF-β complex and MMPs. Transforming growth factor beta_sentence_70

Integrins αVβ6 and αVβ3 are suggested to simultaneously bind the latent TGF-β1 complex and proteinases, simultaneous inducing conformational changes of the LAP and sequestering proteases to close proximity. Transforming growth factor beta_sentence_71

Regardless of involving MMPs, this mechanism still necessitate the association of integrins and that makes it a non proteolytic pathway. Transforming growth factor beta_sentence_72

Signaling pathways Transforming growth factor beta_section_11

Canonical signaling: The SMAD pathway Transforming growth factor beta_section_12

Smads are a class of intracellular signalling proteins and transcription factors for the TGF-β family of signalling molecules. Transforming growth factor beta_sentence_73

This pathway conceptually resembles the Jak-STAT signal transduction pathway characterized in the activation of cytokine receptors implicated, for example, in the B cell isotype switching pathway. Transforming growth factor beta_sentence_74

As previously stated, the binding of the TGF-β ligand to the TGF-β receptor, the type 2 receptor kinase phosphorylates and activates the type 1 receptor kinase that activates a signaling cascade. Transforming growth factor beta_sentence_75

In the case of Smad, receptor-activated Smads are phosphorylated by the type 1 TGF-β receptor kinase, and these go on to complex with other Smads, which is able to translocate into the cell nucleus to induce transcription of different effectors. Transforming growth factor beta_sentence_76

More specifically, activated TGF-β complexes bind to the type 2 domain of the TGF-β receptor which then recruits and phosphorylates a type 1 receptor. Transforming growth factor beta_sentence_77

The type 1 receptor then recruits and phosphorylates a receptor regulated SMAD (R-SMAD). Transforming growth factor beta_sentence_78

The R-SMAD then binds to the common SMAD (coSMAD) SMAD4 and forms a heterodimeric complex. Transforming growth factor beta_sentence_79

This complex then enters the cell nucleus where it acts as a transcription factor for various genes, including those to activate the mitogen-activated protein kinase 8 pathway, which triggers apoptosis. Transforming growth factor beta_sentence_80

The SMAD pathway is regulated by feedback inhibition. Transforming growth factor beta_sentence_81

SMAD6 and SMAD7 may block type I receptors. Transforming growth factor beta_sentence_82

There is also substantial evidence that TGF-β-dependent signaling via the SMAD-3 pathway is responsible for many of the inhibitory functions of TGF-β discussed in later sections and thus it is implicated in oncogenesis. Transforming growth factor beta_sentence_83

The Smads are not the only TGFß-regulated signaling pathways. Transforming growth factor beta_sentence_84

Non-Smad signaling proteins can initiate parallel signaling that eventually cooperate with the Smads or crosstalk with other major signaling pathways. Transforming growth factor beta_sentence_85

Among them, the mitogen-activated protein kinase (MAPK) family that include the extracellular-regulated kinases (ERK1 and 2), Jun N-terminal kinases (JNKs) and p38 MAPK play an important role in the TGFß signaling. Transforming growth factor beta_sentence_86

ERK 1 and 2 are activated via the Raf - Ras - MEK1/2 pathway induced by mitogenic stimuli such as epidermal growth factor, whereas the JNK and p38 MAPK are activated by the MAPK kinase, activated themselves by the TGFß-activated kinase-1 (TAK1) upon stress stimuli. Transforming growth factor beta_sentence_87

Apoptosis via the DAXX pathway Transforming growth factor beta_section_13

TGF-β induces apoptosis, or programmed cell death, in human lymphocytes and hepatocytes. Transforming growth factor beta_sentence_88

The importance of this function is clear in TGF-β deficient mice which experience hyperproliferation and unregulated autoimmunity. Transforming growth factor beta_sentence_89

In a separate apoptotic pathway from the association of death-associated protein 6 (DAXX) with the death receptor Fas, there is evidence of association and binding between DAXX and type 2 TGF-β receptor kinase, wherein DAXX binds to the C-terminal region of the type 2 TGF-β receptor. Transforming growth factor beta_sentence_90

The exact molecular mechanism is unknown, but as a general overview, DAXX is then phosphorylated by homeodomain-interacting protein kinase 2 (HIPK2), which then activates apoptosis signal-inducing kinase 1 (ASK1), which goes on to activate the Jun amino-terminal kinase (JNK) pathway and thus apoptosis as seen in the left panel of the adjacent image. Transforming growth factor beta_sentence_91

Effects on immune cells Transforming growth factor beta_section_14

T lymphocytes Transforming growth factor beta_section_15

TGF-β1 plays a role in the induction from CD4+ T cells of both induced Tregs (iTregs), which have a regulatory function, and Th17 cells, which secrete pro-inflammatory cytokines. Transforming growth factor beta_sentence_92

TGF-β1 alone precipitates the expression of Foxp3 and Treg differentiation from activated T helper cells, and the mechanism for this differentiation is unknown for both induced T regulatory cells as well as natural T regulatory cells. Transforming growth factor beta_sentence_93

In mouse models, the effect of TGF-β1 appears to be age-dependent. Transforming growth factor beta_sentence_94

Studies show that neutralization of TGF-β1 in vitro inhibits the differentiation of helper T cells into Th17 cells. Transforming growth factor beta_sentence_95

The role of TGF-β1 in the generation of Th17 cells goes against its dominant conceptualization as an anti-inflammatory cytokine; however, the shared requirement between inflammatory and anti-inflammatory immune cells suggests that an imbalance between these two cell types can be an important link to autoimmunity. Transforming growth factor beta_sentence_96

Co-activation by IL-6 from activated dendritic cells, which serves to activate the transcription factor STAT3, is required in addition to TGF-β1 for the differentiation of Th17 cells. Transforming growth factor beta_sentence_97

However, the molecular mechanism of Th17 differentiation is not well understood. Transforming growth factor beta_sentence_98

Because Th17 cells are distinct from Th1 and Th2 lineages in that they have been shown to be capable of regulatory functions, this is further evidence of TGF-β1's regulatory function in the immune system. Transforming growth factor beta_sentence_99

B lymphocytes Transforming growth factor beta_section_16

TGF-β has mainly inhibitory effects on B lymphocytes. Transforming growth factor beta_sentence_100

TGF-β inhibits B cell proliferation. Transforming growth factor beta_sentence_101

The exact mechanism is unknown, but there is evidence that TGF-β inhibits B cell proliferation by inducing the transcription factor Id3, inducing expression of cyclin-dependent kinase inhibitor 21 (a regulator of cell cycle progression through the G1 and S phase), and repressing other key regulatory genes such as c-myc and ATM. Transforming growth factor beta_sentence_102

CD40, a key surface molecule in the activation of the innate immune response, can induce Smad7 expression to reverse the growth inhibition of B cells induced by TGF-β. Transforming growth factor beta_sentence_103

TGF-β also blocks B cell activation and promotes class switching IgA in both human and mouse B cells and has an otherwise inhibitory function for antibody production. Transforming growth factor beta_sentence_104

TGF-β also induces apoptosis of immature or resting B cells; the mechanism is unknown, but may overlap with its anti-proliferation pathway. Transforming growth factor beta_sentence_105

TGF-β has been shown to downregulate c-myc as it does in the inhibition of B cell proliferation. Transforming growth factor beta_sentence_106

It is also known to induce NF-κB inhibitor IKBa, inhibiting NF-κB activation. Transforming growth factor beta_sentence_107

NF-κB is a transcription factor that regulates the production of cytokines like IL-1, TNF-a, and defensins, although its function in apoptosis may be separate from this function. Transforming growth factor beta_sentence_108

Macrophages Transforming growth factor beta_section_17

The general consensus in the literature is that TGF-β stimulates resting monocytes and inhibits activated macrophages. Transforming growth factor beta_sentence_109

For monocytes, TGF-β has been shown to function as a chemoattractant as well as an upregulator of inflammatory response. Transforming growth factor beta_sentence_110

However, TGF-β has also been shown to downregulate inflammatory cytokine production in monocytes and macrophages, likely by the aforementioned inhibition of NF-κB. Transforming growth factor beta_sentence_111

This contradiction may be due to the fact that the effect of TGF-β has been shown to be highly context-dependent. Transforming growth factor beta_sentence_112

TGF-β is thought to play a role in alternative macrophage activation seen in lean mice, and these macrophages maintain an anti-inflammatory phenotype. Transforming growth factor beta_sentence_113

This phenotype is lost in obese mice, who have not only more macrophages than lean mice but also classically activated macrophages which release TNF-α and other pro-inflammatory cytokines that contribute to a chronically pro-inflammatory milieu. Transforming growth factor beta_sentence_114

Cell cycle Transforming growth factor beta_section_18

TGF-β plays a crucial role in the regulation of the cell cycle by blocking progress through G1 phase. Transforming growth factor beta_sentence_115

TGF-β causes synthesis of p15 and p21 proteins, which block the cyclin:CDK complex responsible for retinoblastoma protein (Rb) phosphorylation. Transforming growth factor beta_sentence_116

Thus, TGF-β blocks advancement through the G1 phase of the cycle. Transforming growth factor beta_sentence_117

In doing so, TGF-β suppresses expression of c-myc, a gene which is involved in G1 cell cycle progression. Transforming growth factor beta_sentence_118

Clinical significance Transforming growth factor beta_section_19

Cancer Transforming growth factor beta_section_20

In normal cells, TGF-β, acting through its signaling pathway, stops the cell cycle at the G1 stage to stop proliferation, induce differentiation, or promote apoptosis. Transforming growth factor beta_sentence_119

In many cancer cells, parts of the TGF-β signaling pathway are mutated, and TGF-β no longer controls the cell. Transforming growth factor beta_sentence_120

These cancer cells proliferate. Transforming growth factor beta_sentence_121

The surrounding stromal cells (fibroblasts) also proliferate. Transforming growth factor beta_sentence_122

Both cells increase their production of TGF-β. Transforming growth factor beta_sentence_123

This TGF-β acts on the surrounding stromal cells, immune cells, endothelial and smooth-muscle cells. Transforming growth factor beta_sentence_124

It causes immunosuppression and angiogenesis, which makes the cancer more invasive. Transforming growth factor beta_sentence_125

TGF-β also converts effector T-cells, which normally attack cancer with an inflammatory (immune) reaction, into regulatory (suppressor) T-cells, which turn off the inflammatory reaction. Transforming growth factor beta_sentence_126

Normal tissue integrity is preserved by feedback interactions between different cell types that express adhesion molecules and secrete cytokines. Transforming growth factor beta_sentence_127

Disruption of these feedback mechanisms in cancer damages a tissue. Transforming growth factor beta_sentence_128

When TGF-β signaling fails to control NF-κB activity in cancer cells, this has at least two potential effects: first, it enables the malignant tumor to persist in the presence of activated immune cells, and second, the cancer cell outlasts immune cells because it survives in the presence of apoptotic, and anti-inflammatory mediators. Transforming growth factor beta_sentence_129

Heart disease Transforming growth factor beta_section_21

One animal study suggests that cholesterol suppresses the responsiveness of cardiovascular cells to TGF-β and its protective qualities, thus allowing atherosclerosis and heart disease to develop, while statins, drugs that lower cholesterol levels, may enhance the responsiveness of cardiovascular cells to the protective actions of TGF-β. Transforming growth factor beta_sentence_130

TGF-β is involved in regeneration of zebrafish heart. Transforming growth factor beta_sentence_131

Marfan syndrome Transforming growth factor beta_section_22

TGF-β signaling also likely plays a major role in the pathogenesis of Marfan syndrome, a disease characterized by disproportionate height, arachnodactyly, ectopia lentis and heart complications such as mitral valve prolapse and aortic enlargement increasing the likelihood of aortic dissection. Transforming growth factor beta_sentence_132

While the underlying defect in Marfan syndrome is faulty synthesis of the glycoprotein fibrillin I, normally an important component of elastic fibers, it has been shown that the Marfan syndrome phenotype can be relieved by addition of a TGF-β antagonist in affected mice. Transforming growth factor beta_sentence_133

This suggests that while the symptoms of Marfan syndrome may seem consistent with a connective tissue disorder, the mechanism is more likely related to reduced sequestration of TGF-β by fibrillin. Transforming growth factor beta_sentence_134

Loeys–Dietz syndrome Transforming growth factor beta_section_23

TGF-β signaling is also disturbed in Loeys–Dietz syndrome which is caused by mutations in the TGF-β receptor. Transforming growth factor beta_sentence_135

Obesity and diabetes Transforming growth factor beta_section_24

TGF-β/SMAD3 signaling pathway is important in regulating glucose and energy homeostasis and might play a role in diabetic nephropathy. Transforming growth factor beta_sentence_136

As noted above in the section about macrophages, loss of TGF-β signaling in obesity is one contributor to the inflammatory milieu generated in the case of obesity. Transforming growth factor beta_sentence_137

Induced T regulatory cells (iTreg), stimulated by TGF-β in the presence of IL-2, suppressed the development of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS) via a Foxp3 and IL-10 mediated response. Transforming growth factor beta_sentence_138

This suggests a possible role for TGF-β and iTreg in the regulation and treatment of MS. Transforming growth factor beta_sentence_139

Decreased levels of TGF-β have been observed in patients diagnosed with multiple sclerosis. Transforming growth factor beta_sentence_140

Its role in multiple sclerosis can be explained due to TGF-β role in regulating apoptosis of Th17 cells. Transforming growth factor beta_sentence_141

When TGF-β levels decrease, they are unable to induce Th17 cells apoptosis. Transforming growth factor beta_sentence_142

Th17 cells secretes TNF-α, which induces demyelination of the oligodendroglial via TNF receptor 1. Transforming growth factor beta_sentence_143

The decreased TGF-β levels lead to increased Th17 cells and subsequently increased TNFα levels. Transforming growth factor beta_sentence_144

As a result, demyelination of neurons occurs. Transforming growth factor beta_sentence_145

TGF-β have also been observed to induce oligodendrocyte (myelin sheath producing cells) growth. Transforming growth factor beta_sentence_146

Hence, the decreased TGF-β levels during MS may also prevent remyelination of neurons. Transforming growth factor beta_sentence_147

Other Transforming growth factor beta_section_25

Higher concentrations of TGF-β are found in the blood and cerebrospinal fluid of patients with Alzheimer's disease as compared to control subjects, suggesting a possible role in the neurodegenerative cascade leading to Alzheimer's disease symptoms and pathology. Transforming growth factor beta_sentence_148

Overactive TGF-β pathway, with an increase of TGF-β2, was reported in the studies of patients suffering from keratoconus. Transforming growth factor beta_sentence_149

There is substantial evidence in animal and some human studies that TGF-β in breast milk may be a key immunoregulatory factor in the development of infant immune response, moderating the risk of atopic disease or autoimmunity. Transforming growth factor beta_sentence_150

Skin aging is caused in part by TGF-β, which reduces the subcutaneous fat that gives skin a pleasant appearance and texture. Transforming growth factor beta_sentence_151

TGF-β does this by blocking the conversion of dermal fibroblasts into fat cells; with fewer fat cells underneath to provide support, the skin becomes saggy and wrinkled. Transforming growth factor beta_sentence_152

Subcutaneous fat also produces cathelicidin, which is a peptide that fights bacterial infections. Transforming growth factor beta_sentence_153

See also Transforming growth factor beta_section_26

Transforming growth factor beta_unordered_list_1

  • Anita Roberts, a molecular biologist who made pioneering observations of TGF-βTransforming growth factor beta_item_1_3

Credits to the contents of this page go to the authors of the corresponding Wikipedia page: growth factor beta.