scholarly journals Autocrine/paracrine TGFβ1 is required for the development of epidermal Langerhans cells

2007 ◽  
Vol 204 (11) ◽  
pp. 2545-2552 ◽  
Author(s):  
Daniel H. Kaplan ◽  
Ming O. Li ◽  
Matthew C. Jenison ◽  
Warren D. Shlomchik ◽  
Richard A. Flavell ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Langerhans Cells ◽  
Transforming Growth Factor ◽  
Artificial Chromosome ◽  
Accessory Cells ◽  
Epidermal Dendritic Cells ◽  
Deficient Mice ◽  
Tgf Β1 ◽  
Epidermal Langerhans Cells

Langerhans cells (LCs) are bone marrow (BM)–derived epidermal dendritic cells (DCs) that develop from precursors found in the dermis. Epidermal LCs are absent in transforming growth factor (TGF) β1-deficient mice. It is not clear whether TGFβ1 acts directly on LC precursors to promote maturation or whether it acts on accessory cells, which in turn affect LC precursors. In addition, the physiologic source of TGFβ1 is uncertain because BM chimera experiments showed that neither hematopoietic nor nonhematopoietic-derived TGFβ1 is required for LC development. To address these issues, we created mice transgenic for a bacterial artificial chromosome (BAC) containing the gene for human Langerin into which Cre recombinase had been inserted by homologous recombination (Langerin-Cre). These mice express Cre selectively in LCs, and they were bred to floxed TGFβRII and TGFβ1 mice, thereby generating mice with LCs that either cannot respond to or generate TGFβ1, respectively. Langerin-Cre TGFβRII mice had substantially reduced numbers of epidermal LCs, demonstrating that TGFβ1 acts directly on LCs in vivo. Interestingly, Langerin-Cre TGFβ1 mice also had very few LCs both in the steady state and after BM transplantation. Thus, TGFβ1 derived from LCs acts directly on LCs through an autocrine/paracrine loop, and it is required for LC development and/or survival.

scholarly journals Expansion of senescent megakaryocyte-lineage cells maintains CML cell leukemogenesis

2020 ◽  
Vol 4 (24) ◽  
pp. 6175-6188
Author(s):  
Yamato Tanabe ◽  
Shimpei Kawamoto ◽  
Tomoiku Takaku ◽  
Soji Morishita ◽  
Atsushi Hirao ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
Fusion Gene ◽  
Cell Number ◽  
Hematopoietic Stem ◽  
Enhanced Production ◽  
Tgf Β1

Abstract BCR-ABL, an oncogenic fusion gene, plays a central role in the pathogenesis of chronic myeloid leukemia (CML). Oncogenic signaling induces oncogene-induced senescence and senescence-associated secretory phenotype (SASP), which is characterized by enhanced production of various cytokines. BCR-ABL gene transduction confers senescent phenotype in vitro; however, the in vivo relevance of senescence has not been explored in this context. Transplantation of BCR-ABL–expressing hematopoietic stem/progenitor cells caused CML in mice with an increase in bone marrow BCR-ABL+CD41+CD150+ leukemic megakaryocyte-lineage (MgkL) cells, which exhibited enhanced senescence-associated β-galactosidase staining and increased expression of p16 and p21, key molecules that are crucially involved in senescence. Moreover, knockout of p16 and p21 genes reduced both BCR-ABL–induced abnormal megakaryopoiesis and the maintenance of CML cell leukemogenic capacity, as evidenced by attenuated leukemogenic capacity at secondary transplantation. The expression of transforming growth factor-β1 (TGF-β1), a representative SASP molecule, was enhanced in the leukemic MgkL cells, and TGF-β1 inhibition attenuated CML cell leukemogenic capacity both in vitro and in vivo. Furthermore, BCR-ABL–expressing MgkL cells displayed enhanced autophagic activity, and autophagy inhibition reduced bone marrow MgkL cell number and prolonged the survival of CML mice, which had transiently received the tyrosine kinase inhibitor, imatinib, earlier. Thus, BCR-ABL induced the expansion of senescent leukemic MgkL cells, which supported CML leukemogenesis by providing TGF-β1.

scholarly journals Absence of integrin-mediated TGFβ1 activation in vivo recapitulates the phenotype of TGFβ1-null mice

2007 ◽  
Vol 176 (6) ◽  
pp. 787-793 ◽  
Author(s):  
Zhiwei Yang ◽  
Zhenyu Mu ◽  
Branka Dabovic ◽  
Vladimir Jurukovski ◽  
Dawen Yu ◽  
...  
Keyword(s):  
Immune System ◽  
Growth Factor ◽  
Langerhans Cells ◽  
Transforming Growth Factor ◽  
Rgd Sequence ◽  
Tgfβ Receptors ◽  
Thrombospondin 1 ◽  
Tgf Β1 ◽  
Multifunctional Cytokine

The multifunctional cytokine transforming growth factor (TGF) β1 is secreted in a latent complex with its processed propeptide (latency-associated peptide [LAP]). TGFβ1 must be functionally released from this complex before it can engage TGFβ receptors. One mechanism of latent TGFβ1 activation involves interaction of the integrins αvβ6 and αvβ8 with an RGD sequence in LAP; other putative latent TGFβ1 activators include thrombospondin-1, oxidants, and various proteases. To assess the contribution of RGD-binding integrins to TGFβ1 activation in vivo, we created a mutation in Tgfb1 encoding a nonfunctional variant of the RGD sequence (RGE). Mice with this mutation (Tgfb1RGE/RGE) display the major features of Tgfb1−/− mice (vasculogenesis defects, multiorgan inflammation, and lack of Langerhans cells) despite production of normal levels of latent TGFβ1. These findings indicate that RGD-binding integrins are requisite latent TGFβ1 activators during development and in the immune system.

Accelerated Repair of Vascular Injury in Diabetes by TGF-β1 Modified Hematopoietic Stem Cells (HSC).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1398-1398
Author(s):  
Stephen Bartelmez ◽  
Francis W Ruscetti ◽  
Patrick Iversen ◽  
Ashay Bhatwadekar ◽  
Maria Grant
Keyword(s):  
Bone Marrow ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Diabetic Patients ◽  
Retinal Vessels ◽  
Hematopoietic Stem ◽  
Migratory Response ◽  
Cd34 Cells ◽  
Tgf Β1

Abstract Previously, we demonstrated that a transient blockade of endogenous transforming growth factor-beta type 1 (TGF-β1) in murine and human HSC accelerates bone marrow engraftment while dramatically reducing the number of HSC needed for long-term reconstitution. CD34+ cells give rise to endothelial progenitor cells (EPC) and have been shown to participate in the repair of damaged vasculature. CXCR4 is the receptor for stromal derived factor (SDF-1), a chemoattractant released by ischemic tissue that guides EPCs to damaged sites. In this study, we examined levels of TGF- β1 mRNA in CD34+ blood and bone marrow (BM) cells of diabetic and non diabetic individuals. We also treated CD34+ cells of diabetic and nondiabetic origin with antisense phosphorodiamidate morpholino oligomers (PMOs) to TGF-β1 and examined surface expression of CXCR-4, migratory response to SDF-1 as well as in vivo reparative function in a model of retinal ischemic injury. Our results show that CD34+ EPC from the blood of diabetic patients are markedly defective in their ability to repair damaged retinal vessels compared to control cells in contrast to CD34+ cells from the diabetic BM. Diabetic CD34+EPC from blood express elevated levels of TGF-β1 mRNA and have a blunted migratory response to SDF-1 compared to controls (p<0.05 and p<0.01 respectively). Transient (2–4 days) blockade of endogenous TGF-β1 using PMOs to TGF- β1 in diabetic CD34+/EPC increases CXCR-4 expression in these cells, enhances their migratory prowess and restores their ability to repair damaged retinal vessels. This approach is an enhanced autologous stem cell therapy based on a well studied, rapid and reversible modification of bone marrow CD34+EPCs derived from the diabetic patient.

Transforming Growth Factor-β1 (TGF-β1) Induces Thrombopoietin From Bone Marrow Stromal Cells, Which Stimulates the Expression of TGF-β Receptor on Megakaryocytes and, in Turn, Renders Them Susceptible to Suppression by TGF-β Itself With High Specificity

Blood ◽  
1999 ◽  
Vol 94 (6) ◽  
pp. 1961-1970 ◽  
Author(s):  
Sumio Sakamaki ◽  
Yasuo Hirayama ◽  
Takuya Matsunaga ◽  
Hiroyuki Kuroda ◽  
Toshiro Kusakabe ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
High Specificity ◽  
Transforming Growth Factor Β1 ◽  
Lineage Specificity ◽  
Β Receptor ◽  
Tgf Β1

Abstract The present study was designed to test the concept that platelets release a humoral factor that plays a regulatory role in megakaryopoiesis. The results showed that, among various hematoregulatory cytokines examined, transforming growth factor-β1 (TGF-β1) was by far the most potent enhancer of mRNA expression of bone marrow stromal thrombopoietin (TPO), a commitment of lineage specificity. The TPO, in turn, induced TGF-β receptors I and II on megakaryoblasts at the midmegakaryopoietic stage; at this stage, TGF-β1 was able to arrest the maturation of megakaryocyte colony-forming units (CFU-Meg). This effect was relatively specific when compared with its effect on burst-forming unit-erythroid (BFU-E) or colony-forming unit–granulocyte-macrophage (CFU-GM). In patients with idiopathic thrombocytopenic purpura (ITP), the levels of both TGF-β1 and stromal TPO mRNA were correlatively increased and an arrest of megakaryocyte maturation was observed. These in vivo findings are in accord with the aforementioned in vitro results. Thus, the results of the present investigation suggest that TGF-β1 is one of the pathophysiological feedback regulators of megakaryopoiesis.

scholarly journals TGF-β1 maintains suppressor function and Foxp3 expression in CD4+CD25+ regulatory T cells

2005 ◽  
Vol 201 (7) ◽  
pp. 1061-1067 ◽  
Author(s):  
Julien C. Marie ◽  
John J. Letterio ◽  
Marc Gavin ◽  
Alexander Y. Rudensky
Keyword(s):  
Transforming Growth Factor ◽  
Foxp3 Expression ◽  
Regulatory Function ◽  
Suppressor Activity ◽  
Thymic Development ◽  
Immunosuppressive Action ◽  
Deficient Mice ◽  
Tgf Β1 ◽  
Cell Maintenance

Transforming growth factor (TGF)-β1 is a major pluripotential cytokine with a pronounced immunosuppressive effect and its deficiency results in lethal autoimmunity in mice. However, mechanisms of its immunosuppressive action are not completely understood. Here, we report that TGF-β1 supports the maintenance of Foxp3 expression, regulatory function, and homeostasis in peripheral CD4+CD25+ regulatory T (T reg) cells, but is not required for their thymic development. We found that in 8–10-d-old TGF-β1–deficient mice, peripheral, but not thymic, T reg cells are significantly reduced in numbers. Moreover, our experiments suggest that a defect in TGF-β–mediated signaling in T reg cells is associated with a decrease in Foxp3 expression and suppressor activity. Thus, our results establish an essential link between TGF-β1 signaling in peripheral T reg cells and T reg cell maintenance in vivo.

scholarly journals A Role for Endogenous Transforming Growth Factor β1 in Langerhans Cell Biology:  The Skin of   Transforming Growth Factor β1 Null Mice Is Devoid of  Epidermal Langerhans Cells

1996 ◽  
Vol 184 (6) ◽  
pp. 2417-2422 ◽  
Author(s):  
Teresa A. Borkowski ◽  
John J. Letterio ◽  
Andrew G. Farr ◽  
Mark C. Udey
Keyword(s):  
Growth Factor ◽  
Epidermal Cell ◽  
Cell Biology ◽  
Langerhans Cells ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Cell Suspensions ◽  
Wasting Syndrome ◽  
Tgf Β1 ◽  
Epidermal Langerhans Cells

Transforming growth factor β1 (TGF-β1) regulates leukocytes and epithelial cells. To determine whether the pleiotropic effects of TGF-β1, a cytokine that is produced by both keratinocytes and Langerhans cells (LC), extend to epidermal leukocytes, we characterized LC (the epidermal contingent of the dendritic cell [DC] lineage) and dendritic epidermal T cells (DETC) in TGF-β1 null (TGF-β1 −/−) mice. I-A+ LC were not detected in epidermal cell suspensions or epidermal sheets prepared from TGF-β1 −/− mice, and epidermal cell suspensions were devoid of allostimulatory activity. In contrast, TCR-γδ+ DETC were normal in number and appearance in TGF-β1 −/− mice and, importantly, DETC represented the only leukocytes in the epidermis. Immunolocalization studies revealed CD11c+ DC in lymph nodes from TGF-β1 −/− mice, although gp40+ DC were absent. Treatment of TGF-β1 −/− mice with rapamycin abrogated the characteristic inflammatory wasting syndrome and prolonged survival indefinitely, but did not result in population of the epidermis with LC. Thus, the LC abnormality in TGF-β1 −/− mice is not a consequence of inflammation in skin or other organs, and LC development is not simply delayed in these animals. We conclude that endogenous TGF-β1 is essential for normal murine LC development or epidermal localization.

Transforming Growth Factor-β1 (TGF-β1) Induces Thrombopoietin From Bone Marrow Stromal Cells, Which Stimulates the Expression of TGF-β Receptor on Megakaryocytes and, in Turn, Renders Them Susceptible to Suppression by TGF-β Itself With High Specificity

Blood ◽  
1999 ◽  
Vol 94 (6) ◽  
pp. 1961-1970 ◽  
Author(s):  
Sumio Sakamaki ◽  
Yasuo Hirayama ◽  
Takuya Matsunaga ◽  
Hiroyuki Kuroda ◽  
Toshiro Kusakabe ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
High Specificity ◽  
Transforming Growth Factor Β1 ◽  
Lineage Specificity ◽  
Β Receptor ◽  
Tgf Β1

The present study was designed to test the concept that platelets release a humoral factor that plays a regulatory role in megakaryopoiesis. The results showed that, among various hematoregulatory cytokines examined, transforming growth factor-β1 (TGF-β1) was by far the most potent enhancer of mRNA expression of bone marrow stromal thrombopoietin (TPO), a commitment of lineage specificity. The TPO, in turn, induced TGF-β receptors I and II on megakaryoblasts at the midmegakaryopoietic stage; at this stage, TGF-β1 was able to arrest the maturation of megakaryocyte colony-forming units (CFU-Meg). This effect was relatively specific when compared with its effect on burst-forming unit-erythroid (BFU-E) or colony-forming unit–granulocyte-macrophage (CFU-GM). In patients with idiopathic thrombocytopenic purpura (ITP), the levels of both TGF-β1 and stromal TPO mRNA were correlatively increased and an arrest of megakaryocyte maturation was observed. These in vivo findings are in accord with the aforementioned in vitro results. Thus, the results of the present investigation suggest that TGF-β1 is one of the pathophysiological feedback regulators of megakaryopoiesis.

scholarly journals Transforming Growth Factor β1, in the Presence of Granulocyte/Macrophage Colony-stimulating Factor and Interleukin 4, Induces Differentiation of Human Peripheral Blood Monocytes into Dendritic Langerhans Cells

1998 ◽  
Vol 187 (6) ◽  
pp. 961-966 ◽  
Author(s):  
Frederic Geissmann ◽  
Catherine Prost ◽  
Jean-Paul Monnet ◽  
Michel Dy ◽  
Nicole Brousse ◽  
...  
Keyword(s):  
Langerhans Cells ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Interleukin 4 ◽  
Colony Stimulating Factor ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Tgf Β1

Langerhans cells (LCs) are dendritic cells (DCs) that are present in the epidermis, bronchi, and mucosae. Although LCs originate in bone marrow, little is known about their lineage of origin. In this study, we demonstrate that in vitro LCs may originate from monocytes. Adult peripheral blood CD14+ monocytes differentiate into LCs (CD1a+, E-cadherin+, cutaneous lymphocyte-associated antigen+, Birbeck granules+, Lag+) in the presence of granulocyte/macrophage colony-stimulating factor, interleukin 4, and transforming growth factor β1 (TGF-β1). This process occurs with virtually no cell proliferation and is not impaired by 30 Gy irradiation. Selection of monocyte subpopulations is ruled out since monocyte-derived DCs can further differentiate into LCs. Our data suggest that in vivo LC differentiation may be induced peripherally, from a nonproliferating myeloid precursor, i.e., the monocyte, in response to a TGF-β1–rich microenvironment, as found in the skin and epithelia. Therefore, the monocyte may represent a circulating precursor critical to the immune response in vivo.

scholarly journals Regorafenib-Attenuated, Bleomycin-Induced Pulmonary Fibrosis by Inhibiting the TGF-β1 Signaling Pathway

2021 ◽  
Vol 22 (4) ◽  
pp. 1985
Author(s):  
Xiaohe Li ◽  
Ling Ma ◽  
Kai Huang ◽  
Yuli Wei ◽  
Shida Long ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
In Vivo Experiments ◽  
Age Related ◽  
And Migration ◽  
Tgf Β1

Idiopathic pulmonary fibrosis (IPF) is a fatal and age-related pulmonary disease. Nintedanib is a receptor tyrosine kinase inhibitor, and one of the only two listed drugs against IPF. Regorafenib is a novel, orally active, multi-kinase inhibitor that has similar targets to nintedanib and is applied to treat colorectal cancer and gastrointestinal stromal tumors in patients. In this study, we first identified that regorafenib could alleviate bleomycin-induced pulmonary fibrosis in mice. The in vivo experiments indicated that regorafenib suppresses collagen accumulation and myofibroblast activation. Further in vitro mechanism studies showed that regorafenib inhibits the activation and migration of myofibroblasts and extracellular matrix production, mainly through suppressing the transforming growth factor (TGF)-β1/Smad and non-Smad signaling pathways. In vitro studies have also indicated that regorafenib could augment autophagy in myofibroblasts by suppressing TGF-β1/mTOR (mechanistic target of rapamycin) signaling, and could promote apoptosis in myofibroblasts. In conclusion, regorafenib attenuates bleomycin-induced pulmonary fibrosis by suppressing the TGF-β1 signaling pathway.

scholarly journals Store-operated calcium entry suppressed the TGF-β1/Smad3 signaling pathway in glomerular mesangial cells

2017 ◽  
Vol 313 (3) ◽  
pp. F729-F739 ◽  
Author(s):  
Sarika Chaudhari ◽  
Weizu Li ◽  
Yanxia Wang ◽  
Hui Jiang ◽  
Yuhong Ma ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Nuclear Translocation ◽  
Mesangial Cells ◽  
Underlying Mechanism ◽  
Glomerular Mesangial Cells ◽  
Critical Pathway ◽  
Smad3 Phosphorylation ◽  
Tgf Β1

Our previous study demonstrated that the abundance of extracellular matrix proteins was suppressed by store-operated Ca2+entry (SOCE) in mesangial cells (MCs). The present study was conducted to investigate the underlying mechanism focused on the transforming growth factor-β1 (TGF-β1)/Smad3 pathway, a critical pathway for ECM expansion in diabetic kidneys. We hypothesized that SOCE suppressed ECM protein expression by inhibiting this pathway in MCs. In cultured human MCs, we observed that TGF-β1 (5 ng/ml for 15 h) significantly increased Smad3 phosphorylation, as evaluated by immunoblot. However, this response was markedly inhibited by thapsigargin (1 µM), a classical activator of store-operated Ca2+channels. Consistently, both immunocytochemistry and immunoblot showed that TGF-β1 significantly increased nuclear translocation of Smad3, which was prevented by pretreatment with thapsigargin. Importantly, the thapsigargin effect was reversed by lanthanum (La3+; 5 µM) and GSK-7975A (10 µM), both of which are selective blockers of store-operated Ca2+channels. Furthermore, knockdown of Orai1, the pore-forming subunit of the store-operated Ca2+channels, significantly augmented TGF-β1-induced Smad3 phosphorylation. Overexpression of Orai1 augmented the inhibitory effect of thapsigargin on TGF-β1-induced phosphorylation of Smad3. In agreement with the data from cultured MCs, in vivo knockdown of Orai1 specific to MCs using a targeted nanoparticle small interfering RNA delivery system resulted in a marked increase in abundance of phosphorylated Smad3 and in nuclear translocation of Smad3 in the glomerulus of mice. Taken together, our results indicate that SOCE in MCs negatively regulates the TGF-β1/Smad3 signaling pathway.

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