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Anita B. Roberts - One of the best experts on this subject based on the ideXlab platform.
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Beta 2-microglobulin-deficient background ameliorates lethal phenotype of the TGF-Beta 1 null mouse.
Journal of immunology (Baltimore Md. : 1950), 1999Co-Authors: Shigetoshi Kobayashi, Jerrold M. Ward, Kunihiro Yoshida, John J. Letterio, Glenn Longenecker, Linda Yaswen, Barbara Mittleman, Edna Mozes, Anita B. Roberts, Stefan KarlssonAbstract:TGF-Beta 1 null (TGF-Beta1-/-) mice die at 3-4 wk of age and show an autoimmune inflammatory phenotype associated with enhanced expression of both class I and II MHC molecules. To determine the role of MHC class I Ags in the autoimmune manifestations and the inflammation observed in TGF-Beta 1-/- mice, we generated TGF-Beta 1-/- mice in the genetic background of Beta 2-microglobulin deficiency (Beta 2M-/-). TGF-Beta 1-/-;Beta 2M-/- mice had improved survival compared with TGF-Beta 1-/- mice. Histopathological examination showed less severe inflammation, especially in the heart, where Mac-2 reactive macrophages were significantly decreased as compared with TGF-Beta 1-/- mice. In vivo depletion of CD8+ T cells in TGF-Beta 1-/- mice confirmed suppression of inflammation and reduction in the severity of the wasting syndrome. MHC class II mRNA expression in TGF-Beta 1-/-;Beta 2M-/- mice was also lower than that in TGF-Beta 1-/- mice, suggesting reduced systemic inflammation. Autoimmune response as judged by serum Ab titers to ssDNA and 16/6 Id and by immune complex deposits in kidney was reduced in TGF-Beta 1-/-;Beta 2M-/- mice, when compared with that in TGF-Beta 1-/- mice. Our data thus indicate that MHC class I molecules influence the development of the autoimmunity and the inflammation seen in TGF-Beta 1-/- mice and CD8+ T cells may have a contribution to the inflammation in TGF-Beta 1-/- mice.
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Transforming growth factor Beta 1 (TGF-Beta 1) controls expression of major histocompatibility genes in the postnatal mouse: aberrant histocompatibility antigen expression in the pathogenesis of the TGF-Beta 1 null mouse phenotype
Proceedings of the National Academy of Sciences of the United States of America, 1993Co-Authors: Andrew G. Geiser, Ashok B. Kulkarni, Stefan Karlsson, John J. Letterio, Anita B. Roberts, Michael B. SpornAbstract:The phenotype of the transforming growth factor Beta 1 (TGF-Beta 1) null mouse has been previously described and is characterized by inflammatory infiltrates in multiple organs leading to a wasting syndrome and death as early as 3 weeks after birth. Since this phenotype occurs in the absence of any detectable pathogen, potential autoimmune disease mechanisms were investigated. We examined major histocompatibility complex (MHC) mRNA expression in tissues of the TGF-Beta 1 null mouse and found levels of both the class I and class II MHC mRNA elevated compared to normal or TGF-Beta 1 heterozygous littermates. This elevated expression was seen prior to any evidence of inflammatory infiltrates, suggesting a causal relationship between increased MHC expression and activation of immune cell populations. Cell surface expression of MHC molecules was detected by immunohistochemistry and correlated well with mRNA levels. Expression of mRNA for interferon gamma and its receptor was unchanged at the ages when increased MHC expression became apparent. Down-regulation of class I MHC expression by TGF-Beta 1 was also demonstrated in vitro in fibroblasts isolated from TGF-Beta 1 null mice. These findings suggest that one natural function of TGF-Beta 1 is to control expression of both MHC classes. Altered regulation of MHC expression may be a critical step leading to the multifocal inflammation and wasting syndrome seen in the TGF-Beta 1 null mouse. These results suggest potential applications for TGF-Beta in the management of autoimmune disease, allograft rejection, and other problems associated with altered MHC expression.
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Transactivation of the transforming growth factor Beta 1 (TGF-Beta 1) gene by human T lymphotropic virus type 1 tax: a potential mechanism for the increased production of TGF-Beta 1 in adult T cell leukemia.
The Journal of experimental medicine, 1990Co-Authors: Seong-jin Kim, John H. Kehrl, Jack Burton, Craig L. Tendler, Kuan-teh Jeang, David Danielpour, Claire Thévenin, Kyung Young Kim, Michael B. Sporn, Anita B. RobertsAbstract:We examined the effect of the human T lymphotropic virus type 1 (HTLV-I) Tax gene product on the human transforming growth factor Beta 1 (TGF-Beta 1) promoter. Transfection of deleted constructs of the TGF-Beta 1 promoter revealed regions homologous with AP-1 binding sites that were required for Tax-induced transactivation of the TGF-Beta 1 promoter. In addition, we examined the expression and secretion of TGF-Beta in fresh leukemic cells isolated from patients with adult T cell leukemia (ATL) and in HTLV-1-infected T cell lines. We report that fresh leukemic cells from ATL patients constitutively produce high levels of TGF-Beta 1 mRNA and secrete TGF-Beta 1 but not TGF-Beta 2 into the culture medium. In addition, long-term ATL cell lines expressed significant amounts of TGF-Beta 1 mRNA as well as detectable levels of TGF-Beta 1 protein. These results suggest a role for Tax in the upregulation of TGF-Beta 1 in HTLV-I-infected cells.
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Colocalization of TGF-Beta 1 and collagen I and III, fibronectin and glycosaminoglycans during lung branching morphogenesis
Development (Cambridge England), 1990Co-Authors: Ursula I. Heine, Anita B. Roberts, Eliana F. Munoz, Kathleen C. Flanders, Michael B. SpornAbstract:The possible in vivo role of TGF-Beta 1 in regulating various proteins of the extracellular matrix, including fibronectin, collagen I and III, and glycosaminoglycans, was examined by immunohistochemical methods during critical stages of lung morphogenesis in the 11- to 18-day-old mouse embryo. Sections of Bouin-fixed, paraffin-embedded whole embryos were exposed to polyclonal antibodies specific to synthetic peptides present in the precursor part of TGF-Beta 1 (pro-TGF-Beta 1), in the processed TGF-Beta 1 (antibody CC), collagen I and III, fibronectin, followed by the PAP or ABC technique to visualize the location of the antibody. GAG were stained with Alcian Blue 8GX. Our results indicate colocalization of TGF-Beta 1 expression and that of matrix proteins in the developing lung when branching morphogenesis (cleft formation) and tissue stabilization occur. The presence of TGF-Beta 1 at the epithelial-mesenchymal interfaces of stalks and clefts at a time when matrix proteins can first be visualized in these areas, suggests a direct participation of the growth factor in the development of the basic architecture of the lung.
Michael B. Sporn - One of the best experts on this subject based on the ideXlab platform.
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Transforming growth factor Beta 1 (TGF-Beta 1) controls expression of major histocompatibility genes in the postnatal mouse: aberrant histocompatibility antigen expression in the pathogenesis of the TGF-Beta 1 null mouse phenotype
Proceedings of the National Academy of Sciences of the United States of America, 1993Co-Authors: Andrew G. Geiser, Ashok B. Kulkarni, Stefan Karlsson, John J. Letterio, Anita B. Roberts, Michael B. SpornAbstract:The phenotype of the transforming growth factor Beta 1 (TGF-Beta 1) null mouse has been previously described and is characterized by inflammatory infiltrates in multiple organs leading to a wasting syndrome and death as early as 3 weeks after birth. Since this phenotype occurs in the absence of any detectable pathogen, potential autoimmune disease mechanisms were investigated. We examined major histocompatibility complex (MHC) mRNA expression in tissues of the TGF-Beta 1 null mouse and found levels of both the class I and class II MHC mRNA elevated compared to normal or TGF-Beta 1 heterozygous littermates. This elevated expression was seen prior to any evidence of inflammatory infiltrates, suggesting a causal relationship between increased MHC expression and activation of immune cell populations. Cell surface expression of MHC molecules was detected by immunohistochemistry and correlated well with mRNA levels. Expression of mRNA for interferon gamma and its receptor was unchanged at the ages when increased MHC expression became apparent. Down-regulation of class I MHC expression by TGF-Beta 1 was also demonstrated in vitro in fibroblasts isolated from TGF-Beta 1 null mice. These findings suggest that one natural function of TGF-Beta 1 is to control expression of both MHC classes. Altered regulation of MHC expression may be a critical step leading to the multifocal inflammation and wasting syndrome seen in the TGF-Beta 1 null mouse. These results suggest potential applications for TGF-Beta in the management of autoimmune disease, allograft rejection, and other problems associated with altered MHC expression.
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Transactivation of the transforming growth factor Beta 1 (TGF-Beta 1) gene by human T lymphotropic virus type 1 tax: a potential mechanism for the increased production of TGF-Beta 1 in adult T cell leukemia.
The Journal of experimental medicine, 1990Co-Authors: Seong-jin Kim, John H. Kehrl, Jack Burton, Craig L. Tendler, Kuan-teh Jeang, David Danielpour, Claire Thévenin, Kyung Young Kim, Michael B. Sporn, Anita B. RobertsAbstract:We examined the effect of the human T lymphotropic virus type 1 (HTLV-I) Tax gene product on the human transforming growth factor Beta 1 (TGF-Beta 1) promoter. Transfection of deleted constructs of the TGF-Beta 1 promoter revealed regions homologous with AP-1 binding sites that were required for Tax-induced transactivation of the TGF-Beta 1 promoter. In addition, we examined the expression and secretion of TGF-Beta in fresh leukemic cells isolated from patients with adult T cell leukemia (ATL) and in HTLV-1-infected T cell lines. We report that fresh leukemic cells from ATL patients constitutively produce high levels of TGF-Beta 1 mRNA and secrete TGF-Beta 1 but not TGF-Beta 2 into the culture medium. In addition, long-term ATL cell lines expressed significant amounts of TGF-Beta 1 mRNA as well as detectable levels of TGF-Beta 1 protein. These results suggest a role for Tax in the upregulation of TGF-Beta 1 in HTLV-I-infected cells.
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Colocalization of TGF-Beta 1 and collagen I and III, fibronectin and glycosaminoglycans during lung branching morphogenesis
Development (Cambridge England), 1990Co-Authors: Ursula I. Heine, Anita B. Roberts, Eliana F. Munoz, Kathleen C. Flanders, Michael B. SpornAbstract:The possible in vivo role of TGF-Beta 1 in regulating various proteins of the extracellular matrix, including fibronectin, collagen I and III, and glycosaminoglycans, was examined by immunohistochemical methods during critical stages of lung morphogenesis in the 11- to 18-day-old mouse embryo. Sections of Bouin-fixed, paraffin-embedded whole embryos were exposed to polyclonal antibodies specific to synthetic peptides present in the precursor part of TGF-Beta 1 (pro-TGF-Beta 1), in the processed TGF-Beta 1 (antibody CC), collagen I and III, fibronectin, followed by the PAP or ABC technique to visualize the location of the antibody. GAG were stained with Alcian Blue 8GX. Our results indicate colocalization of TGF-Beta 1 expression and that of matrix proteins in the developing lung when branching morphogenesis (cleft formation) and tissue stabilization occur. The presence of TGF-Beta 1 at the epithelial-mesenchymal interfaces of stalks and clefts at a time when matrix proteins can first be visualized in these areas, suggests a direct participation of the growth factor in the development of the basic architecture of the lung.
R. C. Tripathi - One of the best experts on this subject based on the ideXlab platform.
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Trabecular cells express receptors that bind TGF-Beta 1 and TGF-Beta 2: a qualitative and quantitative characterization.
Investigative ophthalmology & visual science, 1993Co-Authors: R. C. Tripathi, N. S. C. Borisuth, S. P. Kolli, B J TripathiAbstract:PURPOSE To quantitate the receptors for transforming growth factor (TGF)-Beta 1 on trabecular cells in culture and to determine the relative affinities of TGF-Beta 1 and TGF-Beta 2 for these receptors. METHODS We quantitated the receptors for TGF-Beta 1 by Scatchard analysis of radioligand binding of 125I-TGF-Beta 1 to cultured porcine trabecular cells. We established the relative affinities of TGF-Beta 1 and TGF-Beta 2 for the receptors by competitive binding of 125I-TGF-Beta 1 with increasing concentrations of the unlabeled TGF-Beta 1 or TGF-Beta 2. We also investigated the binding of 125I-TGF-Beta 1 after pre-treatment of trabecular cells with heparinase. RESULTS Trabecular cells expressed approximately 4,000 high-affinity receptors per cell for TGF-Beta 1, with a dissociation constant (Kd) of 15.8 +/- 7.6 pmol/l. By varying the concentrations of the unlabeled growth factors, we determined that the relative affinities of TGF-Beta 1 and TGF-Beta 2 for the receptors were 16 pmol/l and 50 pmol/l, respectively. Heparinase treatment of the trabecular cells did not change the binding affinity of the receptor for 125I-TGF-Beta 1. CONCLUSIONS Our findings show that trabecular cells express heparinase-insensitive TGF-Beta receptors that have an approximately threefold greater affinity for TGF-Beta 1 than for TGF-Beta 2. Based on the present investigation, together with our previous data on the molecular weights of the binding sites, we conclude that trabecular cells do possess types II and III receptors but not type I receptors.
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Identification and partial characterization of TGF-Beta 1 receptors on trabecular cells.
Investigative ophthalmology & visual science, 1992Co-Authors: N. S. C. Borisuth, B J Tripathi, R. C. TripathiAbstract:By using two specific receptor assays, we identified and partially characterized receptors for transforming growth factor-Beta 1 (TGF-Beta 1) on porcine trabecular cells in vitro. Cultured trabecular cells were incubated with labeled TGF-Beta 1 and analyzed by flow cytometry. Pretreatment with trypsin or preincubation with cold TGF-Beta 1 or a neutralizing antibody to TGF-Beta 1 inhibited the binding of labeled TGF-Beta 1. 125I-TGF-Beta 1 was cross-linked covalently to cell surface receptors on the trabecular cells. By SDS-PAGE and autoradiography, we identified three labeled macromolecular species of receptors, two of which had apparent molecular weights greater than 212 kDa and one of which had an apparent molecular weight of approximately 80-90 kDa under reducing conditions. The low and high molecular weight species probably represent type II and type III TGF-Beta 1 receptors, respectively. At concentrations of 0.5 and 1 ng/ml, activated TGF-Beta 1 caused retraction and a marked decrease in the rate of proliferation and in the motility of trabecular cells in vitro. Our findings implicate TGF-Beta 1 in the modulation of the functional homeostasis of trabecular cells and suggest that the aqueous humor contains a level of TGF-Beta 1 which, once activated, is sufficient to exert a biologic effect on the trabecular meshwork.
B J Tripathi - One of the best experts on this subject based on the ideXlab platform.
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Trabecular cells express receptors that bind TGF-Beta 1 and TGF-Beta 2: a qualitative and quantitative characterization.
Investigative ophthalmology & visual science, 1993Co-Authors: R. C. Tripathi, N. S. C. Borisuth, S. P. Kolli, B J TripathiAbstract:PURPOSE To quantitate the receptors for transforming growth factor (TGF)-Beta 1 on trabecular cells in culture and to determine the relative affinities of TGF-Beta 1 and TGF-Beta 2 for these receptors. METHODS We quantitated the receptors for TGF-Beta 1 by Scatchard analysis of radioligand binding of 125I-TGF-Beta 1 to cultured porcine trabecular cells. We established the relative affinities of TGF-Beta 1 and TGF-Beta 2 for the receptors by competitive binding of 125I-TGF-Beta 1 with increasing concentrations of the unlabeled TGF-Beta 1 or TGF-Beta 2. We also investigated the binding of 125I-TGF-Beta 1 after pre-treatment of trabecular cells with heparinase. RESULTS Trabecular cells expressed approximately 4,000 high-affinity receptors per cell for TGF-Beta 1, with a dissociation constant (Kd) of 15.8 +/- 7.6 pmol/l. By varying the concentrations of the unlabeled growth factors, we determined that the relative affinities of TGF-Beta 1 and TGF-Beta 2 for the receptors were 16 pmol/l and 50 pmol/l, respectively. Heparinase treatment of the trabecular cells did not change the binding affinity of the receptor for 125I-TGF-Beta 1. CONCLUSIONS Our findings show that trabecular cells express heparinase-insensitive TGF-Beta receptors that have an approximately threefold greater affinity for TGF-Beta 1 than for TGF-Beta 2. Based on the present investigation, together with our previous data on the molecular weights of the binding sites, we conclude that trabecular cells do possess types II and III receptors but not type I receptors.
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Identification and partial characterization of TGF-Beta 1 receptors on trabecular cells.
Investigative ophthalmology & visual science, 1992Co-Authors: N. S. C. Borisuth, B J Tripathi, R. C. TripathiAbstract:By using two specific receptor assays, we identified and partially characterized receptors for transforming growth factor-Beta 1 (TGF-Beta 1) on porcine trabecular cells in vitro. Cultured trabecular cells were incubated with labeled TGF-Beta 1 and analyzed by flow cytometry. Pretreatment with trypsin or preincubation with cold TGF-Beta 1 or a neutralizing antibody to TGF-Beta 1 inhibited the binding of labeled TGF-Beta 1. 125I-TGF-Beta 1 was cross-linked covalently to cell surface receptors on the trabecular cells. By SDS-PAGE and autoradiography, we identified three labeled macromolecular species of receptors, two of which had apparent molecular weights greater than 212 kDa and one of which had an apparent molecular weight of approximately 80-90 kDa under reducing conditions. The low and high molecular weight species probably represent type II and type III TGF-Beta 1 receptors, respectively. At concentrations of 0.5 and 1 ng/ml, activated TGF-Beta 1 caused retraction and a marked decrease in the rate of proliferation and in the motility of trabecular cells in vitro. Our findings implicate TGF-Beta 1 in the modulation of the functional homeostasis of trabecular cells and suggest that the aqueous humor contains a level of TGF-Beta 1 which, once activated, is sufficient to exert a biologic effect on the trabecular meshwork.
N. S. C. Borisuth - One of the best experts on this subject based on the ideXlab platform.
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Trabecular cells express receptors that bind TGF-Beta 1 and TGF-Beta 2: a qualitative and quantitative characterization.
Investigative ophthalmology & visual science, 1993Co-Authors: R. C. Tripathi, N. S. C. Borisuth, S. P. Kolli, B J TripathiAbstract:PURPOSE To quantitate the receptors for transforming growth factor (TGF)-Beta 1 on trabecular cells in culture and to determine the relative affinities of TGF-Beta 1 and TGF-Beta 2 for these receptors. METHODS We quantitated the receptors for TGF-Beta 1 by Scatchard analysis of radioligand binding of 125I-TGF-Beta 1 to cultured porcine trabecular cells. We established the relative affinities of TGF-Beta 1 and TGF-Beta 2 for the receptors by competitive binding of 125I-TGF-Beta 1 with increasing concentrations of the unlabeled TGF-Beta 1 or TGF-Beta 2. We also investigated the binding of 125I-TGF-Beta 1 after pre-treatment of trabecular cells with heparinase. RESULTS Trabecular cells expressed approximately 4,000 high-affinity receptors per cell for TGF-Beta 1, with a dissociation constant (Kd) of 15.8 +/- 7.6 pmol/l. By varying the concentrations of the unlabeled growth factors, we determined that the relative affinities of TGF-Beta 1 and TGF-Beta 2 for the receptors were 16 pmol/l and 50 pmol/l, respectively. Heparinase treatment of the trabecular cells did not change the binding affinity of the receptor for 125I-TGF-Beta 1. CONCLUSIONS Our findings show that trabecular cells express heparinase-insensitive TGF-Beta receptors that have an approximately threefold greater affinity for TGF-Beta 1 than for TGF-Beta 2. Based on the present investigation, together with our previous data on the molecular weights of the binding sites, we conclude that trabecular cells do possess types II and III receptors but not type I receptors.
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Identification and partial characterization of TGF-Beta 1 receptors on trabecular cells.
Investigative ophthalmology & visual science, 1992Co-Authors: N. S. C. Borisuth, B J Tripathi, R. C. TripathiAbstract:By using two specific receptor assays, we identified and partially characterized receptors for transforming growth factor-Beta 1 (TGF-Beta 1) on porcine trabecular cells in vitro. Cultured trabecular cells were incubated with labeled TGF-Beta 1 and analyzed by flow cytometry. Pretreatment with trypsin or preincubation with cold TGF-Beta 1 or a neutralizing antibody to TGF-Beta 1 inhibited the binding of labeled TGF-Beta 1. 125I-TGF-Beta 1 was cross-linked covalently to cell surface receptors on the trabecular cells. By SDS-PAGE and autoradiography, we identified three labeled macromolecular species of receptors, two of which had apparent molecular weights greater than 212 kDa and one of which had an apparent molecular weight of approximately 80-90 kDa under reducing conditions. The low and high molecular weight species probably represent type II and type III TGF-Beta 1 receptors, respectively. At concentrations of 0.5 and 1 ng/ml, activated TGF-Beta 1 caused retraction and a marked decrease in the rate of proliferation and in the motility of trabecular cells in vitro. Our findings implicate TGF-Beta 1 in the modulation of the functional homeostasis of trabecular cells and suggest that the aqueous humor contains a level of TGF-Beta 1 which, once activated, is sufficient to exert a biologic effect on the trabecular meshwork.
