scholarly journals Canine Transforming Growth Factor-β Receptor 2-Ig: A Potential Candidate Biologic for Melanoma Treatment That Reverses Transforming Growth Factor-β1 Immunosuppression

2021 ◽  
Vol 8 ◽  
Author(s):  
Hiroto Takeuchi ◽  
Satoru Konnai ◽  
Naoya Maekawa ◽  
Satoshi Takagi ◽  
Hiroshi Ohta ◽  
...  
Keyword(s):  
Growth Factor ◽  
Malignant Melanoma ◽  
Immune Responses ◽  
Cytokine Production ◽  
Transforming Growth Factor ◽  
Immune Systems ◽  
Th1 Cytokine ◽  
Oral Malignant Melanoma ◽  
Canine Melanoma ◽  
Tgf Β1

Cancer cells can evade host immune systems via multiple mechanisms. Transforming growth factor beta 1 (TGF-β1) is an immunosuppressive cytokine that induces regulatory T cell (Tregs) differentiation and is involved in immune evasion mechanisms in cancer. The inhibition of the TGF-β1 signaling pathway can suppress cancer progression and metastasis through the modulation of anticancer immune responses. However, to best of our knowledge, no implementation of treatments targeting TGF-β1 has been reported in dog cancers. This study aimed to examine whether TGF-β1 is upregulated in canine cancers. We measured TGF-β1 concentrations in culture supernatants of canine melanoma cell lines and in serum samples from dogs with oral malignant melanoma. TGF-β1 production was observed in several cell lines, and serum TGF-β1 levels were elevated in dogs with oral malignant melanoma. Interestingly, the addition of recombinant TGF-β1 to canine peripheral blood mononuclear cell cultures decreased Th1 cytokine production and increased differentiation of CD4+CD25+Foxp3+ lymphocytes, suggesting that TGF-β1 is immunosuppressive in canine immune systems. We developed a decoy receptor for TGF-β, namely TGF-βRII-Ig, by identifying an open reading frame of the canine TGFBR2 gene. TGF-βRII-Ig was prepared as a recombinant fusion protein of the extracellular region of canine TGF-βRII and the Fc region of canine IgG-B. As expected, TGF-βRII-Ig bound to TGF-β1. In the presence of TGF-β1, the treatment with TGF-βRII-Ig increased Th1 cytokine production and decreased the differentiation of CD4+CD25+Foxp3+ lymphocytes. Our results suggest that TGF-βRII-Ig competitively inhibits the immunosuppressive effects of TGF-β1 and thereby activates immune responses. This study demonstrated the potential of TGF-βRII-Ig as a novel biologic for canine melanoma.

scholarly journals Elevated plasma levels of transforming growth factor (TGF)-β1 and TGF-β2 in patients with disseminated malignant melanoma

1998 ◽  
Vol 77 (9) ◽  
pp. 1492-1494 ◽  
Author(s):  
K Krasagakis ◽  
D Thölke ◽  
B Farthmann ◽  
J Eberle ◽  
U Mansmann ◽  
...  
Keyword(s):  
Growth Factor ◽  
Malignant Melanoma ◽  
Plasma Levels ◽  
Transforming Growth Factor ◽  
Elevated Plasma ◽  
Tgf Β1

scholarly journals Loss of SOCS3 in T helper cells resulted in reduced immune responses and hyperproduction of interleukin 10 and transforming growth factor–β1

2006 ◽  
Vol 203 (4) ◽  
pp. 1021-1031 ◽  
Author(s):  
Ichiko Kinjyo ◽  
Hiromasa Inoue ◽  
Shinjiro Hamano ◽  
Satoru Fukuyama ◽  
Takeru Yoshimura ◽  
...  
Keyword(s):  
T Cells ◽  
Growth Factor ◽  
Immune Responses ◽  
Leishmania Major ◽  
Transforming Growth Factor ◽  
Dominant Negative ◽  
Conditional Knockout ◽  
Cytokine Signaling ◽  
T Helper ◽  
Tgf Β1

Suppressor of cytokine signaling (SOCS)3 is a major negative feedback regulator of signal transducer and activator of transcription (STAT)3-activating cytokines. Transgenic mouse studies indicate that high levels of SOCS3 in T cells result in type 2 T helper cell (Th2) skewing and lead to hypersensitivity to allergic diseases. To define the physiological roles of SOCS3 in T cells, we generated T cell–specific SOCS3 conditional knockout mice. We found that the mice lacking SOCS3 in T cells showed reduced immune responses not only to ovalbumin-induced airway hyperresponsiveness but also to Leishmania major infection. In vitro, SOCS3-deficient CD4+ T cells produced more transforming growth factor (TGF)-β1 and interleukin (IL)-10, but less IL-4 than control T cells, suggesting preferential Th3-like differentiation. We found that STAT3 positively regulates TGF-β1 promoter activity depending on the potential STAT3 binding sites. Furthermore, chromatin immunoprecipitation assay revealed that more STAT3 was recruited to the TGF-β1 promoter in SOCS3-deficient T cells than in control T cells. The activated STAT3 enhanced TGF-β1 and IL-10 expression in T cells, whereas the dominant-negative form of STAT3 suppressed these. From these findings, we propose that SOCS3 regulates the production of the immunoregulatory cytokines TGF-β1 and IL-10 through modulating STAT3 activation.

Role of circulating angiogenin TGF-β1, VEGF-R1, and VEGF-R2 in metastatic malignant melanoma patients

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 9048-9048
Author(s):  
J. Spano ◽  
R. Mouawad ◽  
S. Vignot ◽  
N. Magné ◽  
D. Khayat
Keyword(s):  
Growth Factor ◽  
Malignant Melanoma ◽  
Transforming Growth Factor ◽  
Metastatic Malignant Melanoma ◽  
Transforming Growth Factor Β1 ◽  
Tumor Burden ◽  
Clinicopathological Parameters ◽  
Healthy Controls ◽  
Melanoma Patients ◽  
Tgf Β1

9048 Background: Malignant melanoma is a disease capable of rapid progression and is associated with high angiogenesis. Thus, investigation of mechanisms involved in metastasis is essential to control this tumor. However, the angiogenesis regulators that are biologically relevant for melanoma are still unknown. We have previously reported that high levels of soluble VEGF in metastatic malignant melanoma (MMM) patients may represent a useful biomarker to predict the effect of biochemotherapy in terms of clinical response. In this study, we evaluate whether soluble levels of angiogenin, transforming growth factor-β1 and VEGFR-1 and -2 play a role in metastatic malignant melanoma patients and to determine if they have any relationship with clinicopathological parameters. Methods: Using a sensitive enzyme-linked immunosorbent assays, angiogenin TGF-β1, VEGF-R1 and VEGF-R2 were measured in sera of 70 patients with a fully documented history of metastatic malignant melanoma in comparison with 30 healthy controls. Results: Pretreatment circulating angiogenin, TGF- β1 VEGF-R1 and VEGF-R2 were detectable, variable in all samples from either melanoma patients or healthy donors Only serum transforming growth factor- β1 levels was significantly higher (p=0.005) in patients compared to healthy controls. No relationship was observed between sex, age or LDH level and all studied parameters. When tumor burden has been taken into consideration, a significant relationship was established between high circulating serum TGF-β1 (p= 0.001) levels and tumor burden were found, Similarly, higher serum VEGFR1 levels were correlated with tumor burden (P = 0.02). Conclusions: The presence of high circulating TGF-β1 and VEGF-R1 in metastatic malignant melanoma patients may prospectively identify high-risk patients with a worse prognosis. In addition, these two parameters may be promising targets for new therapeutic strategies in this pathology. No significant financial relationships to disclose.

scholarly journals JNK and p38 Inhibitors Prevent Transforming Growth Factor-β1-Induced Myofibroblast Transdifferentiation in Human Graves’ Orbital Fibroblasts

2021 ◽  
Vol 22 (6) ◽  
pp. 2952
Author(s):  
Tzu-Yu Hou ◽  
Shi-Bei Wu ◽  
Hui-Chuan Kau ◽  
Chieh-Chih Tsai
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Mapk Pathway ◽  
Transforming Growth Factor Β1 ◽  
Tissue Growth ◽  
Mitogen Activated Protein Kinase ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Western Blots ◽  
Orbital Fibroblasts ◽  
Tgf Β1

Transforming growth factor-β1 (TGF-β1)-induced myofibroblast transdifferentiation from orbital fibroblasts is known to dominate tissue remodeling and fibrosis in Graves’ ophthalmopathy (GO). However, the signaling pathways through which TGF-β1 activates Graves’ orbital fibroblasts remain unclear. This study investigated the role of the mitogen-activated protein kinase (MAPK) pathway in TGF-β1-induced myofibroblast transdifferentiation in human Graves’ orbital fibroblasts. The MAPK pathway was assessed by measuring the phosphorylation of p38, c-Jun N-terminal kinase (JNK), and extracellular-signal-regulated kinase (ERK) by Western blots. The expression of connective tissue growth factor (CTGF), α-smooth muscle actin (α-SMA), and fibronectin representing fibrogenesis was estimated. The activities of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) responsible for extracellular matrix (ECM) metabolism were analyzed. Specific pharmacologic kinase inhibitors were used to confirm the involvement of the MAPK pathway. After treatment with TGF-β1, the phosphorylation levels of p38 and JNK, but not ERK, were increased. CTGF, α-SMA, and fibronectin, as well as TIMP-1 and TIMP-3, were upregulated, whereas the activities of MMP-2/-9 were inhibited. The effects of TGF-β1 on the expression of these factors were eliminated by p38 and JNK inhibitors. The results suggested that TGF-β1 could induce myofibroblast transdifferentiation in human Graves’ orbital fibroblasts through the p38 and JNK pathways.

scholarly journals Exogenous Transforming Growth Factor-β in Brain-Induced Symptoms of Central Fatigue and Suppressed Dopamine Production in Mice

2021 ◽  
Vol 22 (5) ◽  
pp. 2580
Author(s):  
Won Kil Lee ◽  
Yeongyeong Kim ◽  
Heejin Jang ◽  
Joo Hye Sim ◽  
Hye Jin Choi ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Neuroblastoma Cell ◽  
Critical Role ◽  
Central Fatigue ◽  
Chronic Fatigue ◽  
Human Neuroblastoma Cell ◽  
Human Neuroblastoma ◽  
Intracranial Injection ◽  
Tgf Β1

Myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) is one of the most refractory diseases in humans and is characterized by severe central fatigue accompanied with various symptoms that affect daily life, such as impaired memory, depression, and somatic pain. However, the etiology and pathophysiological mechanisms of CFS remain unknown. To investigate the pathophysiological role of transforming growth factor (TGF)-β1, we injected a cytokine into the lateral ventricle of a C57BL/6 mouse. The intracranial injection of TGF-β1 increased the immobility duration in a forced swimming test (FST) and time spent at the closed arm in elevated plus maze (EPM) analysis. The mice injected with TGF-β1 into their brain showed increased sensitivity to pain in a von Frey test, and had a decreased retention time on rotarod and latency time in a bright box in a passive avoidance test. In addition, the serum levels of muscle fatigue biomarkers, lactate dehydrogenase (LDH) and creatine kinase (CK), were significantly increased after administration of TGF-β1. Intracranial injection of TGF-β1 significantly reduced the production of tyrosine hydroxylase (TH) in the ventral tegmental area, accompanied by a decreased level of dopamine in the striatum. The suppression of TH expression by TGF-β1 was confirmed in the human neuroblastoma cell line, SH-SY5Y. These results, which show that TGF-β1 induced fatigue-like behaviors by suppressing dopamine production, suggest that TGF-β1 plays a critical role in the development of central fatigue and is, therefore, a potential therapeutic target of the disease.

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