scholarly journals Interleukin-13 Induces Tissue Fibrosis by Selectively Stimulating and Activating Transforming Growth Factor β1

2001 ◽  
Vol 194 (6) ◽  
pp. 809-822 ◽  
Author(s):  
Chun Geun Lee ◽  
Robert J. Homer ◽  
Zhou Zhu ◽  
Sophie Lanone ◽  
Xiaoman Wang ◽  
...  
Keyword(s):  
Growth Factor ◽  
Serine Protease ◽  
Transforming Growth Factor ◽  
Transgenic Animals ◽  
Transforming Growth Factor Β1 ◽  
Tissue Fibrosis ◽  
Helper Cell Type ◽  
Tgf Β1

Interleukin (IL)-13 is a key mediator of tissue fibrosis caused by T helper cell type 2 inflammation. We hypothesized that the fibrogenic effects of IL-13 are mediated by transforming growth factor (TGF)-β. To test this hypothesis we compared the regulation of TGF-β in lungs from wild-type mice and CC10-IL-13 mice in which IL-13 overexpression causes pulmonary fibrosis. IL-13 selectively stimulated TGF-β1 production in transgenic animals and macrophages were the major site of TGF-β1 production and deposition in these tissues. IL-13 also activated TGF-β1 in vivo. This activation was associated with decreased levels of mRNA encoding latent TGF-β–binding protein-1 and increased mRNA encoding urinary plasminogen activator, matrix metalloproteinase (MMP)-9, and CD44. TGF-β1 activation was abrogated by the plasmin/serine protease antagonist aprotinin. It was also decreased in progeny of crosses of CC10-IL-13 mice and MMP-9 null mice but was not altered in crosses with CD44 null animals. IL-13–induced fibrosis was also significantly ameliorated by treatment with the TGF-β antagonist soluble TGFβR-Fc (sTGFβR-Fc). These studies demonstrate that IL-13 is a potent stimulator and activator of TGF-β1 in vivo. They also demonstrate that this activation is mediated by a plasmin/serine protease- and MMP-9–dependent and CD44-independent mechanism(s) and that the fibrogenic effects of IL-13 are mediated, in great extent, by this TGF-β pathway.

Comparison of Release Profiles of Various Growth Factors from Biodegradable Carriers

1998 ◽  
Vol 530 ◽  
Author(s):  
Y. Tabata ◽  
M. Yamamoto ◽  
Y. Ikada
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
The Body ◽  
Bone Morphogenetic Protein 2 ◽  
Biodegradable Hydrogel ◽  
Tgf Β1

AbstractA biodegradable hydrogel was prepared by glutaraldehyde crosslinking of acidic gelatin with an isoelectric point (IEP) of 5.0 as a carrier to release basic growth factors on the basis of polyion complexation. Basic fibroblast growth factor (bFGF), transforming growth factor β1 (TGF-β1), and bone morphogenetic protein-2 (BMP-2) were sorbed from their aqueous solution into the dried gelatin hydrogels to prepare respective growth factor-incorporating hydrogels. Under an in vitro non-degradation condition, approximately 20 % of incorporated bFGF and TGF-β1 was released from the hydrogels within initial 40 min, followed by no further release, whereas a large initial release of BMP-2 was observed. After subcutaneous implantation of the gelatin hydrogels incorporating 125I-labeled growth factor in the mouse back, the remaining radioactivity was measured to estimate the in vivo release profile of growth factors. Incorporation into gelatin hydrogels enabled bFGF and TGF-β1 to retain in the body for about 15 days and the retention period well correlated with that of the gelatin hydrogel. Taken together, it is likely that the growth factors ionically complexed with acidic gelatin were released in vivo as a result of hydrogel biodegradation. On the contrary, basic BMP-2 did not ionically interact with acidic gelatin, resulting in no sustained released by the present biodegradable carrier system.

scholarly journals Pharmacological inhibition of autophagy by 3-MA attenuates hyperuricemic nephropathy

2018 ◽  
Vol 132 (21) ◽  
pp. 2299-2322 ◽  
Author(s):  
Jinfang Bao ◽  
Yingfeng Shi ◽  
Min Tao ◽  
Na Liu ◽  
Shougang Zhuang ◽  
...  
Keyword(s):  
Growth Factor ◽  
Signaling Pathways ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Growth Factor Receptor ◽  
Nuclear Factor Κb ◽  
Transforming Growth Factor Β1 ◽  
Renal Tissue ◽  
Tgf Β1

Autophagy has been identified as a cellular process of bulk degradation of cytoplasmic components and its persistent activation is critically involved in the renal damage induced by ureteral obstruction. However, the role and underlying mechanisms of autophagy in hyperuricemic nephropathy (HN) remain unknown. In the present study, we observed that inhibition of autophagy by 3-methyladenine (3-MA) abolished uric acid-induced differentiation of renal fibroblasts to myofibroblasts and activation of transforming growth factor-β1 (TGF-β1), epidermal growth factor receptor (EGFR), and Wnt signaling pathways in cultured renal interstitial fibroblasts. Treatment with 3-MA also abrogated the development of HN in vivo as evidenced by improving renal function, preserving renal tissue architecture, reducing the number of autophagic vacuoles, and decreasing microalbuminuria. Moreover, 3-MA was effective in attenuating renal deposition of extracellular matrix (ECM) proteins and expression of α-smooth muscle actin (α-SMA) and reducing renal epithelial cells arrested at the G2/M phase of cell cycle. Injury to the kidney resulted in increased expression of TGF-β1 and TGFβ receptor I, phosphorylation of Smad3 and TGF-β-activated kinase 1 (TAK1), and activation of multiple cell signaling pathways associated with renal fibrogenesis, including Wnt, Notch, EGFR, and nuclear factor-κB (NF-κB). 3-MA treatment remarkably inhibited all these responses. In addition, 3-MA effectively suppressed infiltration of macrophages and lymphocytes as well as release of multiple profibrogenic cytokines/chemokines in the injured kidney. Collectively, these findings indicate that hyperuricemia-induced autophagy is critically involved in the activation of renal fibroblasts and development of renal fibrosis and suggest that inhibition of autophagy may represent a potential therapeutic strategy for HN.

scholarly journals Thrombospondin 1 does not activate transforming growth factor β1 in a chemically defined system or in smooth-muscle-cell cultures

2000 ◽  
Vol 350 (1) ◽  
pp. 291-298 ◽  
Author(s):  
David J. GRAINGER ◽  
Emma K. FROW
Keyword(s):  
Cell Culture ◽  
Smooth Muscle ◽  
Growth Factor ◽  
Matrix Metalloproteinase ◽  
Smooth Muscle Cell ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Matrix Metalloproteinase 2 ◽  
Tgf Β1

The cytokine transforming growth factor β1 (TGF-β1) is secreted in a latent form that has no known biological activity. The conversion of latent TGF-β1 into its biologically active 25kDa form is thought to be an important step in the regulation of TGF-β activity both in cell culture and in vivo. Thrombospondin (TSP)-1, a 360kDa platelet α-granule and extracellular matrix protein, has been shown to participate in TGF-β1 activation. We have used a chemically defined system to examine the mechanism of TSP-1-mediated TGF-β1 activation. However, the addition of two different preparations of TSP-1 to recombinant small latent TGF-β1 in the test tube resulted in only a very small increase in the proportion of the TGF-β1 able to bind to the TGF-β type II receptor: from 0.1% to a maximum of 0.4%. This small effect was not specific for TSP-1: matrix metalloproteinase 2, tissue inhibitor of matrix metalloproteinase 2 and active plasminogen activator inhibitor 1, but not transglutaminase, human serum albumin or immunoglobulin, had quantitatively similar effects on latent TGF-β1. Furthermore, no change in the activity associated with small latent TGF-β1 was noted in either mink lung epithelial cell or rat aortic smooth-muscle cell culture systems in the presence of TSP-1 (or TSP-1-derived peptides). We conclude that TSP-1, either alone or in the presence of cultured smooth-muscle cells (a cell type known to activate latent TGF-β in vitro and in vivo) is unable to activate latent TGF-β1. Any TSP-mediated activation of TGF-β1 must depend on additional factor(s) not present in our systems.

scholarly journals HUBUNGAN ANTARA KADAR TGF-Β1 DENGAN KADAR ALBUMIN DALAM URIN PASIEN DM TIPE-2 DENGAN NEFROPATI DIABETIK

2019 ◽  
Vol 7 (1) ◽  
pp. 73-81
Author(s):  
Elfiani Elfiani ◽  
Rita Halim ◽  
M Haldian Hakir
Keyword(s):  
Diabetic Nephropathy ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Albumin Level ◽  
Cross Sectional ◽  
Integrin Linked Kinase ◽  
Tgf Β1

ABSTRACT Background: Diabetic nephropathy (DN) is a complication of diabetes in the kidney that frequently causes terminal kidney disease. This kidney disease caused by diabetes is a syndrome characterized by albumin in urine (albuminuria). Growth factor-β1 (TGF- β1) is a multifunctional cytokine that controls many biological processes, including immunity, differentiation, tumor suppression, tumor metastasis, aging, migration, wound healing, apoptosis, adipogenesis, and osteogenesis. Previous studies had showed that TGF-β1 plays a role in albuminuria, where TGF-β1 expression in the kidney increases in diabetes patients. Elevation of cytokine level, especially transforming growth factor beta-1 (TGF-β1) that induces the increase of several extra cellular matrices (ECM), i.e. fibronectin, integrin-linked kinase (ILK) and type IV collagen. This TGF-β1 activity causes the accumulation of ECM, which leads to thickened glomerular basement membrane (GBM). Thickening of GBM and changes in kidney structure in the form of hypertrophy and reduced glomerular podocytes caused by apoptosis and attachment in GBM causes protein components to exit through urine (albuminuria). This study aimed to prove the correlation between transforming growth factor-β1 and albumin level in urine of diabetic nephropathy. Metode : This study a observasional with desain Cross-sectional  comparative study. Results: Mean TGF-β1 level in type 2 DM patients with diabetic nephropathy in this study was 47.30 ± 14.70 ng/ml, with similar value between men and women with 43.1 ng/ml and 44.7 ng/ml, respectively. Out of 60 type 2 DM participants with ND, the mean albuminuria level according to ACR was 722.53 ± 1854.96 mg/g. The result of male participants was lower compared to female participants, with 667.8 mg/mg and 777.2 mg/g, respectively. Conclusion: There was insignificant correlation between TGF-β1 in diabetic nephropathy (DN) and albumin level in urine measured using albumin and urine creatinine ratio (ACR) (p = 0.066). Keywords: Diabetic Nephropathy, Albuminuria, TGF-β1   ABSTRAK Latar Belakang : Nefropati diabetik (ND) merupakan komplikasi diabetes pada ginjal yang paling sering menyebabkan terjadinya penyakit ginjal terminal. Penyakit ginjal akibat diabetes ini merupakan sindroma dengan karakteristik terdapatnya albumin dalam urine (albuminuria). Faktor pertumbuhan-β1 (TGF-β1) adalah sebuah sitokin multifungsi yang mengendalikan banyak proses biologis termasuk kekebalan, diferensiasi, tumor supresi, tumor metastasis, penuaan, migrasi, penyembuhan luka, apoptosis, adipogenesis, dan osteogenesis. Sejumlah penelitian sebelumnya menunjukkan bahwa TGF-β1 berperan terhadap terjadinya albuminuria, dimana pasien diabetes didapatkan ekspresi TGF-β1 di ginjal meningkat. Peningkatan kadar cytokine terutama Transforming Growth Factor Beta-1 (TGF-β1) yang menginduksi peningkatan beberapa Extra Cellular Matrix (ECM) antara lain fibronectin, integrin-linked kinase (ILK) dan collagen tipe-IV. Aktifitas TGF-β1 ini menyebabkan akumulasi ECM sehingga terjadi penebalan Glomerular Basement Membrane (GBM). Penebalan dari GBM dan terjadinya perubahan struktur ginjal berupa hipertrofi dan berkurangnya sel-sel podocyte glomerulus akibat kerusakan (apoptosis) dan perlengketan di GBM menyebabkan komponen protein keluar melalui urin (albuminuria). Tujuan penelitian ini untuk membuktikan hubungan antara kadar transforming growth  factor-β1 dengan kadar albumin dalam urin pada Nefropati Diabetik. Metode : Penelitian ini merupakan penelitian Observasional dengan desain Cross-sectional   comparative study. Hasil : Kadar rata-rata TGF-β1 pasien DM tipe-2 dengan Nefropati Diabetik pada penelitian ini adalah 47,30 ± 14,70 ng/ml, tidak jauh berbeda antara laki-laki yaitu 43,1 ng/ml dengan perempuan 44,7 ng/ml. Dari 60 orang responden DM tipe-2 dengan ND pada penelitian ini didapatkan kadar albuminuria rata-rata berdasarkan ACR adalah 722,53 ± 1854,96 mg/g. Responden laki-laki lebih rendah dibanding perempuan yaitu 667,8 mg/g berbanding 777,2 mg/g. Kesimpulan : Tidak terdapat hubungan yang bermakna antara TGF-β1 pada Nefropati Diabetik (ND) dengan kadar albumin dalam urin yang dihitung berdasarkan rasio albumin dan creatinin urin (ACR) (p=0,066). Kata Kunci : Nefropati Diabetik, Albuminuria, TGF-β1

Activation of Transforming Growth Factor β1 (TGF-β1) Released by Platelets Is Enhanced by Shear and Occurs in Platelet-Rich Thrombi In Vivo.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3632-3632
Author(s):  
Jasimuddin Ahamed ◽  
Nathalie Burg ◽  
Christin Janczak ◽  
Jihong Li ◽  
Barry S. Coller
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Thrombus Formation ◽  
Transforming Growth Factor Β1 ◽  
Sharp Contrast ◽  
Luciferase Reporter ◽  
Plasminogen Activator Inhibitor 1 ◽  
Total N ◽  
Tgf Β1

Abstract Platelets contain 40–100 times as much transforming growth factor β1 (TGF-β1) as other cells, and release it as an inactive (latent) complex. Although several TGF-β1 activating factors have been identified in various cell types, it is still not known whether and how platelet TGF-β1 becomes activated in vivo. In the present study, cell-free human washed platelet releasates (supernatant after stimulation with thrombin 0.125U/ml for 5 min) or serum samples were subjected to either stirring (1,200 rpm) in an aggregometer or a shear stress of 1800 s−1 in a cone and plate device at 37°C. Activation of TGF-β1 was analyzed by ELISA and selectively confirmed using a cell-based plasminogen activator inhibitor 1 (PAI-1) luciferase reporter assay. TGF-β1 was maximally released within 5 min after stimulation of platelets with thrombin (80 ± 23 ng/ml; n=3), but only 0.2% was active. TGF-β1 activity increased slowly and progressively under shear, reaching a maximum of ∼5% of total TGF-β1 (4.1 ± 1.5 ng/ml) after 1 h. In sharp contrast, in two experiments conducted without shear, active TGF-β1 constituted 0.04 and 0.2% of total at 0 time and remained nearly the same (0.1 and 0.2% of total) after 2 h. Activation of TGF-β1 in serum under shear occurred more slowly, but also reached a maximum of ∼5% of total at 2 h (4.1 ± 1.3 ng/ml active; 76 ± 14 ng/ml total; n=6). Without shear at 0 time, active TGF-β1 constituted 0.02 and 0.06% of total and at 2 h it was still only 0.05 and 0.07% of total. To asses whether TGF-β1 becomes activated in vivo during thrombosis, we induced thrombi in the carotid arteries of C57/BL mice with ferric chloride (8%) for 3 min and then removed the platelet-rich thrombi that formed after 5 or 120 min. The arteries were excised (∼4 mm) and the thrombi were removed and dispersed in buffer (200 μl) on ice for 1 h. Total TGF-β1 recovered from 5 min thrombi was 3.4 and 4.8 ng/ml and total TGF-β1 recovered from 120 min thrombi was 3.7 and 0.7 ng/ml. Active TGF-β1 could be detected in thrombi after 5 min and constituted 1.7 ± 1.1% of the total TGF-β1 recovered (n=3). After 120 min, active TGF-β1 could also be detected in thrombi and it constituted 5.1 ± 3.0% of the total recovered (p=0.14 compared to 5 min value; n=3). In sharp contrast, only 0.05% of TGF-β1 released by thrombin from mouse platelets in vitro was active without stirring or shear (n=3). These data indicate that shear can dramatically enhance TGF-β1 activation after release from platelets. Moreover, TGF-β1 activation occurs in vivo during platelet-rich thrombus formation and thus platelets may be an important source of active TGF-β1 in cardiovascular disease and wound healing.

scholarly journals Pyrrole-Imidazole Polyamide Targeting Transforming Growth Factor β1 Ameliorates Encapsulating Peritoneal Sclerosis

2012 ◽  
Vol 32 (4) ◽  
pp. 462-472 ◽  
Author(s):  
Kazuo Serie ◽  
Noboru Fukuda ◽  
Shigeki Nakai ◽  
Hiroyuki Matsuda ◽  
Takashi Maruyama ◽  
...  
Keyword(s):  
Growth Factor ◽  
Mrna Expression ◽  
Messenger Rna ◽  
Transforming Growth Factor ◽  
Fluorescein Isothiocyanate ◽  
Transforming Growth Factor Β1 ◽  
Vegf Mrna ◽  
Tgf Β1

ObjectiveEncapsulating peritoneal sclerosis (EPS) is a devastating fibrotic complication in patients treated with peritoneal dialysis (PD). Transforming growth factor β1 (TGF-β1) is a pivotal factor in the induction of EPS.MethodsTo develop pyrrole-imidazole (PI) polyamide, a novel gene silencer, targeted to the TGF-β1 promoter (Polyamide) for EPS, we examined the effects of Polyamide on messenger RNA (mRNA) expression of TGF-β 1, vascular endothelial growth factor (VEGF), and extracellular matrix (ECM) in mesothelial cells in vitro, and on the thickness of injured peritoneum evaluated by histology and high- resolution regional elasticity mapping in rats in vivo.ResultsPolyamide significantly lowered mRNA expression of TGF-β 1 and ECM in vitro. Polyamide labeled with fluorescein isothiocyanate was taken up into the injured peritoneum and was strongly localized in the nuclei of most cells. Polyamide 1 mg was injected intraperitoneally 1 or 3 times in rats receiving a daily intraperitoneal injection of chlorhexidine gluconate and ethanol (CHX) for 14 days. Polyamide significantly suppressed peritoneal thickening and the abundance of TGF-β 1 and fibronectin mRNA, but did not affect expression of VEGF mRNA in the injured peritoneum. Elasticity distribution mapping showed that average elasticity was significantly lower in Polyamide-treated rats than in rats treated solely with CHX.ConclusionsPolyamide suppressed the stiffness, ECM formation, and thickening of the injured peritoneum that occurs during EPS pathogenesis. These data suggest that PI polyamide targeted to the TGF-β 1 promoter will be a specific and feasible therapeutic strategy for patients with EPS.

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 LIM-Only Protein FHL2 Is a Negative Regulator of Transforming Growth Factor β1 Expression

2017 ◽  
Vol 37 (10) ◽  
Author(s):  
Jennifer Dahan ◽  
Florence Levillayer ◽  
Tian Xia ◽  
Yann Nouët ◽  
Catherine Werts ◽  
...  
Keyword(s):  
Growth Factor ◽  
Rna Polymerase Ii ◽  
Gene Transcription ◽  
Wound Repair ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Negative Regulator ◽  
Mesenchymal Transition ◽  
Tgf Β1

ABSTRACT Transforming growth factor β1 (TGF-β1) is a master cytokine in many biological processes, including tissue homeostasis, epithelial-to-mesenchymal transition, and wound repair. Here, we report that four and a half LIM-only protein 2 (FHL2) is a critical regulator of TGF-β1 expression. Devoid of a DNA-binding domain, FHL2 is a transcriptional cofactor that plays the role of coactivator or corepressor, depending on the cell and promoter contexts. We detected association of FHL2 with the TGF-β1 promoter, which showed higher activity in Fhl2 −/− cells than in wild-type (WT) cells in a reporter assay. Overexpression of FHL2 abrogates the activation of the TGF-β1 promoter, whereas the upregulation of TGF-β1 gene transcription correlates with reduced occupancy of FHL2 on the promoter. Moreover, ablation of FHL2 facilitates recruitment of RNA polymerase II on the TGF-β1 promoter, suggesting that FHL2 may be involved in chromatin remodeling in the control of TGF-β1 gene transcription. Enhanced expression of TGF-β1 mRNA and cytokine was evidenced in the livers of Fhl2 −/− mice. We tested the in vivo impact of Fhl2 loss on hepatic fibrogenesis that involves TGF-β1 activation. Fhl2 −/− mice developed more severe fibrosis than their WT counterparts. These results demonstrate the repressive function of FHL2 on TGF-β1 expression and contribute to the understanding of the TGF-β-mediated fibrogenic response.

scholarly journals In vitro and in vivo evidence for shear-induced activation of latent transforming growth factor-β1

Blood ◽  
2008 ◽  
Vol 112 (9) ◽  
pp. 3650-3660 ◽  
Author(s):  
Jasimuddin Ahamed ◽  
Nathalie Burg ◽  
Keiji Yoshinaga ◽  
Christin A. Janczak ◽  
Daniel B. Rifkin ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Thrombus Formation ◽  
Cell Types ◽  
Transforming Growth Factor Β1 ◽  
Disulfide Exchange ◽  
Before And After ◽  
Tgf Β1

Transforming growth factor-β1 (TGF-β1) has potent physiologic and pathologic effects on a variety of cell types at subnanomolar concentrations. Platelets contain 40 times as much TGF-β1 as other cells and secrete it as an inactive (latent) form in complex with latency-associated peptide (LAP), which is disulfide bonded via Cys33 to latent TGF-β binding protein 1 (LTBP-1). Little is known about how latent TGF-β1 becomes activated in vivo. Here we show that TGF-β1 released from platelets or fibroblasts undergoes dramatic activation when subjected to stirring or shear forces, providing a potential mechanism for physiologic control. Thiol-disulfide exchange appears to contribute to the process based on the effects of thiol-reactive reagents and differences in thiol labeling of TGF-β1 before and after stirring or shear. Activation required the presence of LTBP, as TGF-β1 contained in complex with only LAP could not be activated by stirring when studied as either a recombinant purified protein complex or in the platelet releasates or sera of mice engineered to contain an LAP C33S mutation. Release and activation of latent TGF-β1 in vivo was demonstrated in a mouse model 5 minutes after thrombus formation. These data potentially provide a novel mechanism for in vivo activation of TGF-β1.

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