Tgf-beta

Transforming growth factor-beta is a component and prototype of a large family of cytokines that can exert numerous biological processes in a variety of cell types. It is therefore a cytokine that can exhibit different activities depending on the cell type, developmental stage, differentiation and cell cycle position of the target cell.

TGF-beta modulates, among other things, proliferation, apoptosis, activation and differentiation of the corresponding target cells. The most prominent dermatological activities include:

• inhibition of epithelial cell proliferation
• stimulation of extracellular matrix synthesis by fibroblasts
• angiogenesis
• protection of early thymic T cells from cell death and regulation of mature T cells and macrophages.

Due to its broad spectrum of activity, TGF-beta plays a central role in regeneration, immune response and tumorigenesis. The TGF-beta molecules influence, among other things, the control of cell growth and differentiation in reparative processes as well as in the initiation of inflammation through chemotactic effects on inflammatory cells and fibroblasts. TGF has an activating function in radiogenic radiation fibrosis of the skin (see below Cutaneous radiation syndrome).

• TGF-beta is present in 3 isoforms:
  • TGF-beta1(TGFB1 gene)
  • TGF-beta2 (TGFB2 gene)
  • TGF-beta3 (TGFB3 gene).
• Each isoform is encoded by a separate gene on different chromosomes. TGF-beta is present in most cells, but in latent form and may be activated. In wound healing, binding to thrombospondin, which is released by platelets, appears to be essential for activation.
• Two types of membrane receptors (type I and type II receptors) are initially activated by the action of TGF-beta as a ligand. The TGF-beta type I receptor then phosphorylates Smad proteins which, after translocation into the nucleus, specifically regulate target genes. In healthy human skin, the type I and II receptors could be detected in the epidermis, in skin appendages and in vascular cells, but only in a few fibroblasts. In fibroblasts of keloids, an increased expression of TGF-beta 1 and TGF-beta 2 was found compared to normal fibroblasts with unchanged expression of TGF-beta 3. TGF-beta 1 and 2 in particular are regarded as fibrosis-inducing cytokines and are found to be increased in humans in inflammatory altered skin in circumscribed scleroderma and progressive systemic scleroderma.
• During wound healing in humans, the number of dermal fibroblasts expressing TGF-beta receptor type I and II increases compared to normal skin and decreases again as the healing process progresses, but not in hypertrophic scarring.
• Since TGF-beta is a wound healing-promoting cytokine, it is surprising that Smad 3 knock-out mice exhibit significantly accelerated wound healing after injury. The wound healing process is characterized by a release of TGF-beta from degranulating platelets that migrate into the wound area. TGF-beta causes a strong migration of monocytes and neutrophils into the region. These eliminate microorganisms, keep the wound edges clean, but also promote local inflammation through cytokine and protease release, which is not conducive to wound healing.
• Fibroblasts also perform TGF-beta stimulated chemotaxis, proliferate strongly, cause wound edge contraction for better closure and secrete matrix material such as collagen and fibronectin for tissue reconstruction. TGF-beta activates Smad-mediated transcription of the genes for collagen and fibronectin. The leukocytes and fibroblasts that have migrated into the wound area secrete TGF-beta again. As a result, the tissue level of TGF-beta increases and intensifies the migration until a compensatory downregulation of Smad 3 occurs. Only now does the activity of the cells described decrease. At the same time, TGF-beta levels fall and the inhibition of keratinocyte proliferation is lifted. Finally, re-epithelialization of the wound takes place.
• The accelerated wound healing in the absence of TGF-beta or downregulation of Smad 3 is probably due on the one hand to the increased keratinocyte proliferation. On the other hand, the reduced monocyte infiltration, which does not have a negative effect in the absence of wound contamination, prevents the development of inflammation. These two factors appear to more than compensate for the reduced matrix formation. The wounds of Smad-3-knock-outs heal within two days, whereas wild-type mice require an average of four to five days for this process. However, the evaluation of this fact remains difficult. If matrix formation is underrepresented in Smad 3 deficiency, this may be at the expense of stable new tissue. In addition, the defense mechanisms against bacterial contamination are inadequate without the immigration of immune cells.
• Prospects for new drugs: The elucidation of the signaling cascades of TGF-beta and the knowledge of its physiological significance appear to be important for the development of new specific drugs. TGF agonists could be used in hyperproliferative skin diseases such as psoriasis, TGF antagonists in wound healing. Although TGF-beta is not yet available in any dosage form, its use as a drug is certainly a possibility. The same applies to active substances that modify the TGF-beta metabolism or influence the TGF-beta signaling pathway. This includes substances that stimulate or inhibit receptors or those that modulate Smad proteins. The multitude of possible interventions at the various stages of the TGF-beta signaling cascade opens up promising perspectives in the search for new active substances.

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