Transforming growth factor-β1 down-regulates expression of chemokine stromal cell–derived factor-1: functional consequences in cell migration and adhesion

Blood ◽  
2003 ◽  
Vol 102 (6) ◽  
pp. 1978-1984 ◽  
Author(s):  
Natalia Wright ◽  
Teresa Laín de Lera ◽  
Carelia García-Moruja ◽  
Rosa Lillo ◽  
Félix García-Sánchez ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Migration ◽  
Growth Factor ◽  
Stromal Cell ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Hematopoietic Progenitor ◽  
Functional Consequences ◽  
Stromal Cell Derived Factor ◽  
Tgf Β1

Abstract Chemokine stromal cell–derived factor-1 (SDF-1) is expressed by bone marrow (BM) stromal cells and plays key roles in BM cell migration. Modulation of its expression could affect the migratory capacity of cells trafficking the BM, such as hematopoietic progenitor and leukemic cells. Transforming growth factor-β1 (TGF-β1) is present in the BM environment and constitutes a pivotal molecule controlling BM cell proliferation and differentiation. We used the BM stromal cell line MS-5 as a model to investigate whether SDF-1 expression constitutes a target for TGF-β1 regulation and its functional consequences. We show here that TGF-β1 down-regulates SDF-1 expression, both at the mRNA level, involving a decrease in transcriptional efficiency, and at the protein level, as detected in lysates and supernatants from MS-5 cells. Reduction of SDF-1 in supernatants from TGF-β1–treated MS-5 cells correlated with decreased, SDF-1–dependent, chemotactic, and transendothelial migratory responses of the BM model cell lines NCI-H929 and Mo7e compared with their responses to supernatants from untreated MS-5 cells. In addition, supernatants from TGF-β1–exposed MS-5 cells had substantially lower efficiency in promoting integrin α4β1–mediated adhesion of NCI-H929 and Mo7e cells to soluble vascular cell adhesion molecule-1 (sVCAM-1) and CS-1/fibronectin than their untreated counterparts. Moreover, human cord blood CD34+ hematopoietic progenitor cells displayed SDF-1–dependent reduced responses in chemotaxis, transendothelial migration, and up-regulation of adhesion to sVCAM-1 when supernatants from TGF-β1–treated MS-5 cells were used compared with supernatants from untreated cells. These data indicate that TGF-β1–controlled reduction in SDF-1 expression influences BM cell migration and adhesion, which could affect the motility of cells trafficking the bone marrow.

scholarly journals Transforming growth factor-β1 modulates responses of CD34+ cord blood cells to stromal cell-derived factor-1/CXCL12

Blood ◽  
2005 ◽  
Vol 106 (2) ◽  
pp. 485-493 ◽  
Author(s):  
Sunanda Basu ◽  
Hal E. Broxmeyer
Keyword(s):  
Bone Marrow ◽  
Growth Factor ◽  
Cord Blood ◽  
Progenitor Cells ◽  
Stromal Cell ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Cd34 Cells ◽  
Stromal Cell Derived Factor ◽  
Tgf Β1

Abstract Disruption of stromal cell-derived factor-1 (SDF-1/CXCL12 [CXC chemokine ligand 12]) interaction leads to mobilization of stem/progenitor cells from bone marrow to circulation. However, prolonged exposure of CD34+ cells to SDF-1 desensitizes them to SDF-1. So how do cells remain responsive to SDF-1 in vivo when they are continuously exposed to SDF-1? We hypothesized that one or more mechanisms mediated by cytokines exist that could modulate SDF-1 responsiveness of CD34+ cells and the desensitization process. We considered transforming growth factor-β1 (TGF-β1) a possible candidate, since TGF-β1 has effects on CD34+ cells and is produced by stromal cells, which provide niches for maintenance and proliferation of stem/progenitor cells. TGF-β1 significantly restored SDF-1–induced chemotaxis and sustained adhesion responses in cord blood CD34+ cells preexposed to SDF-1. Effects of TGF-β1 were dependent on the dose and duration of TGF-β1 pretreatment. Phosphorylation of extracellular signal-regulated kinase 1 (Erk1)/Erk2 was implicated in TGF-β1 modulation of migratory and adhesion responses to SDF-1. Our results indicate that low levels of TGF-β1 can modulate SDF-1 responsiveness of CD34+ cells and thus may facilitate SDF-1–mediated retention and nurturing of stem/progenitor cells in bone marrow.

scholarly journals Transforming Growth Factor-β1 Abrogates Fas-Induced Growth Suppression and Apoptosis of Murine Bone Marrow Progenitor Cells

Blood ◽  
1997 ◽  
Vol 90 (9) ◽  
pp. 3395-3403 ◽  
Author(s):  
Ingunn Dybedal ◽  
Fengan Guan ◽  
Ole Johan Borge ◽  
Ole Petter Veiby ◽  
Veslemøy Ramsfjell ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Growth Factor ◽  
Progenitor Cells ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Growth Suppression ◽  
Hematopoietic Progenitor Cells ◽  
Hematopoietic Progenitor ◽  
Induced Apoptosis ◽  
Tgf Β1

Abstract Fas, a member of the tumor necrosis factor (TNF ) receptor superfamily is a critical downregulator of cellular immune responses. Proinflammatory cytokines like interferon-γ (IFN-γ) and TNF-α can induce Fas expression and render hematopoietic progenitor cells susceptible to Fas-induced growth suppression and apoptosis. Transforming growth factor-β1 (TGF-β1 ) is an essential anti-inflammatory cytokine, thought to play a key role in regulating hematopoiesis. In the present studies we investigated whether TGF-β1 might regulate growth suppression and apoptosis of murine hematopoietic progenitor cells signaled through Fas. In the presence of TNF, activation of Fas almost completely blocked clonogenic growth of lineage-depleted (Lin−) bone marrow (BM) progenitor cells in response to granulocyte-macrophage colony-stimulating factor (GM-CSF ), CSF-1, or a combination of multiple cytokines. Whereas TGF-β1 alone had no effect or stimulated growth in response to these cytokines, it abrogated Fas-induced growth suppression. Single-cell studies and delayed addition of TGF-β1 showed that the ability of TGF-β1 to inhibit Fas-induced growth suppression was directly mediated on the progenitor cells and not indirect through potentially contaminating accessory cells. Furthermore, TGF-β1 blocked Fas-induced apoptosis of Lin− BM cells, but did not affect Fas-induced apoptosis of thymocytes. TGF-β1 also downregulated the expression of Fas on Lin− BM cells. Thus, TGF-β1 potently and directly inhibits activation-dependent and Fas-mediated growth suppression and apoptosis of murine BM progenitor cells, an effect that appears to be distinct from its ability to induce progenitor cell-cycle arrest. Consequently, TGF-β1 might act to protect hematopoietic progenitor cells from enhanced Fas expression and function associated with proinflammatory responses.

Chemotactic Response Toward Chemokines and Its Regulation by Transforming Growth Factor-β1 of Murine Bone Marrow Hematopoietic Progenitor Cell-Derived Different Subset of Dendritic Cells

Blood ◽  
1999 ◽  
Vol 93 (10) ◽  
pp. 3225-3232 ◽  
Author(s):  
Masafumi Ogata ◽  
Yi Zhang ◽  
Yong Wang ◽  
Meiji Itakura ◽  
Yan-yun Zhang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Primary Immune Response ◽  
Hematopoietic Progenitor Cell ◽  
Hematopoietic Progenitor ◽  
Murine Bone Marrow ◽  
Tgf Β1

Dendritic cells (DCs) are highly specialized antigen-presenting cells that distribute widely in all organs. DCs initiate the primary immune response and activate naive T cells and B cells responsible for the acquired immunity. In this study, CCR7 mRNA was proved to be expressed in DCs and their precursors derived from murine bone marrow-derived hematopoietic progenitor cells (HPCs), whereas CCR1 mRNA was expressed in both CD11b−/dullCD11c+ and CD11b+hiCD11c+ DC precursors. CCR6 mRNA was not detected in any murine DC populations. In agreement with the chemokine receptor mRNA expression by each population in the DC differentiation pathway, SLC (also termed as MIP-3β), one of the ligands for CCR7, strongly and selectively chemoattracted both CD11b−/dullCD11c+ and CD11b+hiCD11c+ DC precursors (days 6 to 7) and more mature DCs (days 13 to 14). We have recently found that transforming growth factor-β1 (TGF-β1), a cytokine that is essential for the appearance of Langerhans cells in the skin, polarizes murine HPCs to generate Langerhans-like cells through monocyte/macrophage differentiation pathway. We observed here that TGF-β1 not only inhibited the expression of CCR7 in DCs and DC precursors derived from HPCs, but also inhibited the migration of these cells in response to SLC. This is the first report describing the chemokine and chemokine receptors responsible for murine DC migration and downregulation of DC migration by TGF-β1.

scholarly journals CD105 Protein Depletion Enhances Human Adipose-derived Stromal Cell Osteogenesis through Reduction of Transforming Growth Factor β1 (TGF-β1) Signaling

2011 ◽  
Vol 286 (45) ◽  
pp. 39497-39509 ◽  
Author(s):  
Benjamin Levi ◽  
Derrick C. Wan ◽  
Jason P. Glotzbach ◽  
Jeong Hyun ◽  
Michael Januszyk ◽  
...  
Keyword(s):  
Growth Factor ◽  
Stromal Cell ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Protein Depletion ◽  
Tgf Β1

scholarly journals Rapid Up-Regulation of α4 Integrin-mediated Leukocyte Adhesion by Transforming Growth Factor-β1

2003 ◽  
Vol 14 (1) ◽  
pp. 54-66 ◽  
Author(s):  
Rubén A. Bartolomé ◽  
Francisco Sanz-Rodrı́guez ◽  
Mar M. Robledo ◽  
Andrés Hidalgo ◽  
Joaquin Teixidó
Keyword(s):  
Cell Migration ◽  
Cell Adhesion ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Human Peripheral Blood ◽  
Transforming Growth Factor Β1 ◽  
Small Gtpase ◽  
Mitogen Activated Protein Kinase ◽  
Intracellular Camp ◽  
Tgf Β1

The α4 integrins (α4β1 and α4β7) are cell surface heterodimers expressed mostly on leukocytes that mediate cell-cell and cell-extracellular matrix adhesion. A characteristic feature of α4 integrins is that their adhesive activity can be subjected to rapid modulation during the process of cell migration. Herein, we show that transforming growth factor-β1 (TGF-β1) rapidly (0.5–5 min) and transiently up-regulated α4 integrin-dependent adhesion of different human leukocyte cell lines and human peripheral blood lymphocytes (PBLs) to their ligands vascular cell adhesion molecule-1 (VCAM-1) and connecting segment-1/fibronectin. In addition, TGF-β1 enhanced the α4 integrin-mediated adhesion of PBLs to tumor necrosis factor-α–treated human umbilical vein endothelial cells, indicating the stimulation of α4β1/VCAM-1 interaction. Although TGF-β1 rapidly activated the small GTPase RhoA and the p38 mitogen-activated protein kinase, enhanced adhesion did not require activation of both signaling molecules. Instead, polymerization of actin cytoskeleton triggered by TGF-β1 was necessary for α4 integrin-dependent up-regulated adhesion, and elevation of intracellular cAMP opposed this up-regulation. Moreover, TGF-β1 further increased cell adhesion mediated by α4 integrins in response to the chemokine stromal cell-derived factor-1α. These data suggest that TGF-β1 can potentially contribute to cell migration by dynamically regulating cell adhesion mediated by α4 integrins.

Down-Regulation of Toll-Like Receptor 4 Expression in Transforming Growth Factor β1 Treated Murine Dendritic Cells: Implications of Maturation Resistant to Lipopolysaccharide.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3803-3803
Author(s):  
Maofang Lin ◽  
Haibo Mou ◽  
Hong Cen
Keyword(s):  
Bone Marrow ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Brdu Incorporation ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Murine Bone Marrow ◽  
Gm Csf ◽  
Tgf Β1

Abstract Evidences accumulated that immature dendritic cell (iDC) could inhibit alloantigen-specific T cell responses and prolong the survival time of allografts. However, the tolerogenic properties of these iDCs were often unstable or inconsistent because of in vivo maturation, such as lipopolysaccharide (LPS) stimulating. Toll-like receptor 4(TLR4) has been reported to act as a receptor for LPS and LPS can stimulate iDC to mature DC (mDC) via TLR4 signal transduction pathway. In this study, we investigated the effects of transforming growth factor β1 on murine bone marrow derived DCs. Murine bone marrow cells were cultured with GM-CSF and TGF-β1 to generate TGF-β1 treated DCs (TGFβ-DCs). Compared to iDCs cultured by GM-CSF alone, the TGFβ-DCs had no significant alterations in ultrastructure after LPS stimulation. Surface expression of CD80, CD86, CD40, MHC-II were inhibited by addition of TGF-β1, especially in CD80, CD86 (p<0.05). Furthermore, the iDCs were sensitive to further maturation in response to LPS by showing increased levels of MHC class II, CD80, CD86 and CD40. In marked contrast, TGF-β1 prevented this LPS-mediated maturation and maintained the cells in the immature state, with low levels of surface costimulatory molecules expression. Using BrdU incorporation method, after 96 h mix lymphocyte reaction, TGFβ-DCs had weaker allogeneic stimulating capacity than iDCs. Importantly, LPS stimulating strongly promoted the allostimulatory capacity of iDCs, whereas only slightly affected TGFβ-DCs. TGFβ-DCs also showed decreased IL-12p70 production and impaired NF-κB activation after LPS stimulation. We also found the expression of TLR4 mRNA on TGFβ-DCs was weaker than that on iDCs by RT-PCR. Moreover, the results of flow cytometry revealed the positive expression percentages of TLR4/MD2 complex on iDCs and TGFβ-DCs were (51.8±3.89% vs. 15.7±4.13%, p<0.01) and the mean fluorescence intensities (MFIs) were (2.37±0.26 vs. 1.36±0.17, p<0.05). These results agreed with previous findings that TGFβ-DCs responded weakly to LPS. In summary, TGFβ-DC is resistant to maturation stimulus (LPS) and might have some correlation with the down-modulation of TLR4 expression.

Transforming Growth Factor-β1 Polarizes Murine Hematopoietic Progenitor Cells to Generate Langerhans Cell-Like Dendritic Cells Through a Monocyte/Macrophage Differentiation Pathway

Blood ◽  
1999 ◽  
Vol 93 (4) ◽  
pp. 1208-1220 ◽  
Author(s):  
Yi Zhang ◽  
Yan-yun Zhang ◽  
Masafumi Ogata ◽  
Pan Chen ◽  
Akihisa Harada ◽  
...  
Keyword(s):  
Growth Factor ◽  
Progenitor Cells ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Hematopoietic Progenitor Cells ◽  
Hematopoietic Progenitor ◽  
Macrophage Differentiation ◽  
Gm Csf ◽  
Tgf Β1 ◽  
E Cadherin

We have recently demonstrated that CD11b−/dullCD11c+ and CD11b+hiCD11c+ dendritic cell (DC) precursor subsets represent two distinct DC differentiation pathways from murine bone marrow lineage-phenotype negative (Lin−)c-kit+ hematopoietic progenitor cells (HPCs) stimulated with granulocyte-macrophage colony-stimulating factor (GM-CSF) + stem cell factor (SCF) + tumor necrosis factor  (TNF). We show here that transforming growth factor-β1 (TGF-β1) significantly inhibits the generation of these CD11b−/dullCD11c+ and CD11b+hiCD11c+ DC precursors. Phenotypically, this inhibitory effect was accompanied by markedly suppressed expression of Ia and CD86 antigens as well as major histocompatibility complex (MHC) class II transactivator (CIITA) and CC-chemokine receptor 7 (CCR7) mRNAs in Lin−c-kit+ HPC cultures stimulated with GM-CSF + SCF + TNF at day 6. TGF-β1 could also suppress mature DC differentiation from CD11b+hiCD11c+ DC precursors, but not the differentiation from CD11b−/dullCD11c+ DC precursors. In the absence of TNF, TGF-β1 markedly suppressed the expression of CIITA and CCR7 mRNAs in GM-CSF + SCF-stimulated Lin−c-kit+ HPCs at either day 6 or day 12 and induced the differentiation solely into monocytes/macrophages as evident in morphology, active phagocytic, and endocytic activities. These cells expressed high levels of F4/80 and E-cadherin antigens, but low or undetectable levels of Ia, CD86, and CD40 molecules. However, upon the stimulation with TNF + GM-CSF, these cells could further differentiate into mature DCs expressing high levels of Ia and E-cadherin, characteristics for Langerhans cells (LCs), and gained the capacity of enhancing allogenic MLR. Taken together, all of these findings suggest that TGF-β1 polarizes murine HPCs to generate LC-like DCs through a monocyte/macrophage differentiation pathway.

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.

Transforming growth factor-β1 regulates macrophage migration via RhoA

Blood ◽  
2006 ◽  
Vol 108 (6) ◽  
pp. 1821-1829 ◽  
Author(s):  
Jun-Sub Kim ◽  
Jae-Gyu Kim ◽  
Mi-Young Moon ◽  
Chan-Young Jeon ◽  
Ha-Young Won ◽  
...  
Keyword(s):  
Cell Migration ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Rho Gtpase ◽  
Initial Period ◽  
Transforming Growth Factor Β1 ◽  
Dominant Negative ◽  
Monocyte Chemoattractant Protein 1 ◽  
Protein Levels ◽  
Tgf Β1

Abstract Brief treatment with transforming growth factor (TGF)–β1 stimulated the migration of macrophages, whereas long-term exposure decreased their migration. Cell migration stimulated by TGF-β1 was markedly inhibited by 10 μg/mL Tat-C3 exoenzyme. TGF-β1 increased mRNA and protein levels of macrophage inflammatory protein (MIP)–1α in the initial period, and these effects also were inhibited by 10 μg/mL Tat-C3 and a dominant-negative (DN)–RhoA (N19RhoA). Cycloheximide, actinomycin D, and antibodies against MIP-1α and monocyte chemoattractant protein-1 (MCP-1) abolished the stimulation of cell migration by TGF-β1. These findings suggest that migration of these cells is regulated directly and indirectly via the expression of chemokines such as MIP-1α and MCP-1 mediated by RhoA in response to TGF-β1. TGF-β1 activated RhoA in the initial period, and thereafter inactivated them, suggesting that the inactivation of RhoA may be the cause of the reduced cell migration in response to TGF-β1 at later times. We therefore attempted to elucidate the molecular mechanism of the inactivation of RhoA by TGF-β1. First, TGF-β1 phosphorylated RhoA via protein kinase A, leading to inactivation of RhoA. Second, wild-type p190 Rho GTPase activating protein (p190RhoGAP) reduced and DN-p190RhoGAP reversed the reduction of cell migration induced by TGF-β, suggesting that it inactivated RhoA via p190 Rho GAP.

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