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Transformin Growth Factor-β
Published in Jason Kelley, Cytokines of the Lung, 2022
The TGF-β receptor-ligand system encompasses a truly complex pattern of cross-reactive ligands and receptors (for review, see Cheifetz et al., 1990). There are at least three TGF-β receptors, termed receptors I, II, and III. All three may be expressed by the same cell type simultaneously. Importantly, the several receptor proteins are not cognate receptors for TGF-β types of the same numerical order.
The Host Response to Grafts and Transplantation Immunology
Published in Julius P. Kreier, Infection, Resistance, and Immunity, 2022
These promoter region polymorphisms, because they polarize responses toward cell-mediated or antibody-mediated responses, may influence allograft rejection. Thus, an individual who has a genetically encoded tendency to make higher levels of interleukin-10 and lower levels of interferon-y has a tendency to polarize toward antibody mediated responses. Studies have shown that transplant receipts with the genetic profile for high interferon-γ/low interleukin-10 production have significantly more frequent and more severe acute rejection episodes. In contrast, individuals with the genetic profile for low interferon-γ/high interleukin-10 production have significantly longer graft survival with fewer acute rejection episodes. Some transplant surgeons are now beginning to use cytokine promoter region allele typing to tailor immunosuppressive drug therapy for a specific recipient. Cytokine promoter region alleles also may influence chronic rejection. Individuals who have a high TGF-β production phenotype have more severe chronic rejection in a recent study. As mentioned earlier, TGF-β is a potent smooth muscle mitogen and probably accounts for some of the smooth muscle cell proliferation in the intima of vessels in the graft that occurs during chronic rejection. TGF-β is also involved in the fibrosis seen in the lesions.
Transforming Growth Factor-β/Smad Signaling in Myocardial Disease
Published in Shyam S. Bansal, Immune Cells, Inflammation, and Cardiovascular Diseases, 2022
Claudio Humeres, Nikolaos G. Frangogiannis
Most tissues contain latent stores of TGF-β that can be activated following injury. It has been suggested that activation of a small fraction of the preexisting latent TGF-β stores is sufficient to trigger a maximal cellular response1. Following activation, TGF-βs bind to their receptors, initiating signaling. All members of the TGF-β superfamily signal through characteristic combinations of type I and type II TGF-β receptors (TβRs)2,3. In humans, there are seven type I TβRs [also known as activin-like receptor kinase (ALK) 1–7] and five type II TβRs (TβRII, ActRII, ActRIIB, AMHRII, and BMPRII)4. Activins typically signal through ALK4 or ALK7 after binding to ActRII or ActRIIB. The bone morphogenetic protein (BMP) family signals through a number of combinations, including one of the type I receptors ALK1, ALK2, ALK3, and ALK6 and one of the ActRII, ActRIIB, and BMPRII type II TβRs5,6. All three TGF-β isoforms (TGF-β1, -β2, and -β3) act through a single type II receptor (TβRII). In most cells, TGF-β isoforms signal through ALK5-TβRII activation7; however, in endothelial cells, TGF-β is known to transduce key signals though the ALK1/TβRII pathway8,9. Although some studies have suggested that the TGF-β/ALK1 cascade can also be activated in non–endothelial cell types, including fibro-blasts10 and macrophages11, the pathophysiological role of these pathways is unclear.
The potential association between metabolic syndrome and risk of post-surgical adhesion
Published in Archives of Physiology and Biochemistry, 2023
Gordon A Ferns, Milad Shahini Shams Abadi, Mohammad-Hassan Arjmand
In pathological conditions, a decrease of fibrinolysis activity leads to incomplete degradation of fibrin matrix as a result of the imbalance between plasminogen inhibitor activator (PAI) and tPA towards PAI, promotes post-surgical adhesion (Ivarsson et al. 1998). In the absence of an effective fibrinolytic response, a strong fibrin gel matrix leading to fibrotic adhesion. Moreover, an increased inflammatory response and chronic recruitment of immune cells leads to oxidative stress, and an increased expression of inflammatory cytokines such as interleukin 6 (IL6), tumour necrosis factor α (TNF-α) and transforming growth factor β (TGF-β). These cytokines attract more immune cells to the site and up-regulate molecular mechanisms leading to the expression of fibrotic genes (Saed & Diamond 2004). TGF-β regulates the expression of many fibrotic genes such as PAI and collagens that are the main molecules in fibrotic scars pathogenesis (Saed et al. 1999). Additionally, TGF-β decreases matrix metalloprotease (MMP) activity and increases tissue inhibitor metalloprotease (TIMP) leading to enhanced ECM deposition through a decrease of degradation of ECM which is important in stimulating fibrosis (Chegini et al. 2001). The most important events leading to post-surgical adhesion is summarised in Figure 1.
Combined targeting of soluble latent TGF-ß and a solid tumor-associated antigen with adapter CAR T cells
Published in OncoImmunology, 2022
Niels Werchau, Bettina Kotter, Elvira Criado-Moronati, Andre Gosselink, Nicole Cordes, Dominik Lock, Simon Lennartz, Carolin Kolbe, Nora Winter, Karin Teppert, Fabian Engert, Brian Webster, Joerg Mittelstaet, Daniel Schaefer, Peter Mallmann, Michael R. Mallmann, Dominik Ratiu, Mario Assenmacher, Thomas Schaser, Michael von Bergwelt-Baildon, Pierre Abramowski, Andrew D. Kaiser
One cytokine that exhibits immunosuppression in the TME is TGF-β. TGF-β is a pleiotropic cytokine and is associated with immune evasion by inhibiting cytotoxic T cell responses, interfering with antigen presentation, or by inducing a Treg phenotype.35–37 Different approaches to target TGF-β are under investigation, e.g. neutralizing antibodies, ligand traps, or small molecules.38 In addition, targeting LAP by monoclonal antibodies elicited an anti-tumor response in various tumor models by reducing, e.g. TGF-β bioavailability and immunosuppressive T cells.39 Thus, latent TGF-β could also be an attractive target for CAR T cell therapy. The clinical relevance of latent TGF-β is further supported by a study of Hawinkels et al. investigating latent TGF-β levels locally in tumor tissue. Significantly higher levels of latent TGF-β were found in homogenates of gastric cancer patients as compared to adjacent control tissue.40 In our study, LAP, as a part of latent TGF-β, was found on cancer tissue sections from ovaries. LAP was associated with desmoplastic areas invaded by EpCAM+ tumor cells. In addition, we found that LAP expression is co-localized with surface markers of fibroblasts (CD90) and integrins (CD49a).
Betaine attenuates sodium arsenite-induced renal dysfunction in rats
Published in Drug and Chemical Toxicology, 2022
Sumedha Sharma, Tajpreet Kaur, Ashwani Kumar Sharma, Balbir Singh, Devendra Pathak, Harlokesh Narayan Yadav, Amrit Pal Singh
Renal fibrosis is an important component of progressive renal disease and is characterized by increased extracellular matrix production and infiltration of inflammatory cells. Transforming growth factor-β (TGF-β) is a dimeric peptide and regulates cell proliferation and differentiation. Arsenic has been noted to increase renal TGF-β level in vitro as well as in vivo (Zhang et al.2014; Adil et al.2015; Meng et al.2016). Hydroxyproline is the major component of collagen and its increase indicates fibrosis in tissues. Our results witnessed a marked increase in renal hydroxyproline content when rats are subjected to arsenic treatment. Moreover, picrosirius red staining for collagen revealed extensive fibrosis in kidneys of arsenic intoxicated rats, which was abrogated with betaine treatment.