Transforming Growth Factor Beta-1 (TGF B-1)

What Is Transforming Growth Factor Beta-1(TGF B-1)

TGF B-1 is involved in maintenance of tissue homeostasis. It helps regulate effects in the innate immune system. TGFb1 is an immune suppressor (although it can upregulate the immune system in some instances - see below) and is often chronically over-expressed in disease states, including cancer, fibrosis and inflammation. It is moderately to extremely high in Chronic Inflammatory Response Syndrome due to water-damaged buildings (CIRS).

Prolonged elevations of TGF-beta 1 levels can create conditions where tissue remodeling and autoimmune transformation become more likely. Although Tgf-beta 1 can be high in various disease process, the idea should be to find and deal with the cause of over-active TGF b-1, rather than simply lowering it from a high state to a normalized state.

Details on TGF B-1 and the transforming growth factor-β (TGFβ) superfamily of cytokines.

The TGFB superfamily of cytokines consists of TGFβs, activins, inhibins, Nodal, bone morphogenetic proteins (BMPs), anti-Müllerian hormone (AMH; also known as Müllerian-inhibiting factor) as well as growth and differentiation factors (GDFs), is found in all multicellular organisms. The TGFβs are involved in many cellular processes, including growth inhibition, cell migration, invasion, epithelial-mesenchymal transition (EMT), extracellular matrix (ECM) remodeling and immune-suppression. However, although normally dynamically regulated and involved in maintenance of tissue homeostasis, TGFβs are often chronically over-expressed in disease states, including cancer, fibrosis and inflammation, and this excessive production of TGFβ drives disease progression by modulating cell growth, migration or phenotype. The TGFβ signalling pathway has therefore become a popular target for drug development.

As a growth factor, TGF-beta-1 regulates immune and tissue cell growth and proliferation. TGF beta-1 is thought of as an immune suppressant (anti-inflammatory) but this is not true if you are turning on  TH 17 cells  and there is conversion of T regulatory cells in tissue to pathogenic T cells at the same time. Research shows it has a role in activation of autoimmunity as well as suppressing autoimmunity. TGF-beta, together with IL-6 and IL-21, promotes Th17 cell development. Th17 cells have been identified as a lineage distinct from Th1 and Th2 cells, and are required for induction of several autoimmune diseases, including collagen-induced arthritis, experimental autoimmune encephalitis (EAE), and inflammatory bowel disease (IBD), and also for the ability to clear bacterial infections of the intestine and the airways.

It appears TGF beta-1 is not immune suppressive if T-reg cells (known by their CD4+/CD25+ cell surface markers) are in normal range. If T-regs are low, TGF- beta 1 can transform them into pathogenic T-cells in tissues, as happens in CIRS cases. This transformation may depend in part on IL-6. The net result is a positive feedback loop in which more TGF-beta gets produced.

This TGF beta-1-induced conversion of T-regs into pathogenic T cells has been shown to be reduced using Losartan at a dose of 25 mg twice daily. VIP is also used to lower TGF beta-1. There are additionally quite a few herbs and supplements that can reduce TGF-beta-1.

Use of losartan is contraindicated in some renal transplant patients. In patients with diabetic nephropathy, angiotensin-converting–enzyme (ACE) inhibitors reduce blood pressure and the progression of nephropathy but approximately 10 percent of patients have side effects that cause the discontinuation of ACE-inhibitor therapy. Losartan is an angiotensin II–receptor antagonist that may have similar efficacy but fewer side effects. However, research has shown losartan may induce renal insufficiency.

Prolonged elevations of TGF-beta 1 levels can create conditions where tissue remodeling and autoimmune transformation become more likely.

Research indicates that members of the arginine‐glycine‐aspartic acid tripeptide (RGD)‐binding integrin receptor subfamily appear to be the primary mediators of latent TGFβ activation in vivo in many organ injury states that lead to fibrosis.

The TGF-Beta Signaling Pathway can be viewed here.

TGF beta-1 Actions

• Elevated TGF beta-1 with low CD4+CD25+ cells drives production of antibodies to gliadin and cardiolipin. It may drive production of other antibodies also. You can test for these antibodies. If you don't test I suggest removing gluten from your diet until you are well at least.
• Inhibits IL-1 and IL-2 dependent T cell proliferation.
• Inhibits activation of both T helper and cytotoxic T cells.
• Inhibits secretion of IFN-gamma, TNF-alpha and other interleukins.
• Downregulates the expression of cytokine receptors on activated T cells.
• Inhibits the proliferation of macrophages and monocytes and limits their production of reactive oxygen and nitrogen species.
• Induces Foxp3 expresion.
• Necessary for the conversion of Th0 cells to Treg cells in the presence of antigen stimulation of the appropriate level.
• TGF beta stimulates EGF receptors
• Decreased levels of glutathione will stimulate production of TGF-β, and when glutathione is replenished, the production of TGF-β will be decreased.

 

Results of high TGF beta-1

With high levels of TGF beta-1 you see lung symptoms, neurological problems, learning disability,  resting tremors, unusual seizures.  (Low levels and high levels may both be related to autoimmune disease.) Normal levels keep it in check. In mice if they have no TGF beta-1 it induces autoimmune disease.

The common autoantibody production most commonly seen with CIRS involves antigliadin antibodies of the IgG class and anticardiolipins of the IgM class. There are other autoantibodies made that react to gliadin and cardiolipin. The two listed are the most common and tested for by all labs. Others can be tested at Cyrex Labs.

As an aside - You also see low MSH levels with mold illness and low MSH is also associated with autoimmunity: 1) Food protein-induced enterocolitis syndrome (FPIES) 2) Gliadin autoantibody positivity and 3) True celiac disease are also seen with CIRS (mold illness). These illnesses are not antibody illness. These are an autoantibody (antibodies against individual's own proteins) illness.

Lower TGF-B-1 and you get rid of the autoimmune problems usually. Need it in normal levels as too low will induce autoimmunity too.

Look at TGF B-1 in ulcerative colitis inflammatory bowel diseases. If TGF b-1 is high, lower the TGF b-1 and the inflammatory bowel diseases should disappear.

High TGF Beta-1 is associated with loss of hair (associated with development of catigen hairs – hair follicules that have stopped growing and actually may be dead,  sudden onset of inflammatory response and high levels of TGF beat-1 can cause injury to the organ of corti causing tinnitus, nystagmus, and hearing loss.

TGFb1 impacts the kidneys and can create renal fibrosis.

Lowering TGFb1 enhances neurogenesis and muscle regeneration.

For a list of supplements and herbs that lower TGF b-1 please go to Treatment of CIRS.

TGFβ mediates the immunosuppressive differentiation of T cells

Treatment of naive T cells with TGFβ induces the expression of the transcription factor forkhead box protein P3 (FOXP3), which drives the phenotypical conversion of a naive T cell to a TReg cell-Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3.

Interestingly, TReg cell-induced suppression of the adaptive immune response is also mediated through the expression of TGFβ. The high levels of TGF-beta 1 appear to damage T-regulatory cell function that usually prevent autoimmune conditions such as seen in asthma and multiple sclerosis.

High TGF beta-1 is seen in autoimmiune illness as well as T-regulatory cells that are too low. This is important in pathogenesis of autoimmunity. Rising levels of TGF beta-1 will cause the migration of t-regulatory cells into tissue to suppress inflammation and suppress autoimmunity. In the tissue if the levels of the retinoic acid orphan receptor (ROR) are too low bad things will happen to our friends the T reg cells: they are converted to pathogenic T cells that make more TGF beta-1 and low T regs. The tissue basis of uncontrolled inflammation is an additional burden for CIRS pts.

According to Dr Shoemaker, the highest levels of TGF beta-1 are seen in the haplotype 11-3-52B who are hypermobile.

Normal is <2382 pg/ml.

 

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