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K C Flanders - One of the best experts on this subject based on the ideXlab platform.
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TGF Beta 1 but not TGF Beta 2 or TGF Beta 3 is differentially present in epithelial cells of advanced pulmonary fibrosis an immunohistochemical study
American Journal of Respiratory Cell and Molecular Biology, 1996Co-Authors: Nasreen Khalil, K C Flanders, Robert Oconnor, Helmut UnruhAbstract:Although it is recognized that three isoforms of transforming growth factor-Beta (TGF-Beta) exist in mammals, their expression, distribution, and function in injury and repair are not well characterized. Using immunohistochemistry and antibodies to synthetic peptides of TGF-Beta 1, TGF-Beta 2, and TGF-Beta 3, we determined the distribution of TGF-Beta isoforms in lung sections with acute and chronic lesions of idiopathic pulmonary fibrosis (IPF), chronic asbestosis and hypersensitivity pneumonitis, as well as non-specific pneumonitis. In lung sections with advanced pulmonary fibrosis and honeycombing, irrespective of the diagnosis, TGF-Beta 1 was prominently expressed in epithelial cells and macrophages and was found to be associated with the extracellular matrix. In lungs with early lesions of IPF and only inflammatory changes, TGF-Beta 1 was present in alveolar macrophages but TGF-Beta 1 was not present in epithelial cells. Small amounts of matrix-associated TGF-Beta 1 were present subepithelially in areas of lung sections from patients with IPF with minimal inflammation and no fibrosis. In normal lungs with no evidence of inflammation or fibrosis TGF-Beta 1 was not seen in alveolar macrophages, epithelial cells, or extracellularly. TGF-Beta 2 and TGF-Beta 3 were expressed in alveolar macrophages, epithelial cells, and smooth muscle cells of vessels and bronchi of normal lungs and lungs with both inflammatory and fibrotic changes. Our findings suggest that while TGF-Beta 2 and TGF-Beta 3 are ubiquitously expressed in the lung, TGF-Beta 1 is expressed in epithelial cells of fibrotic lungs where the presence of TGF-Beta 1 is not disease-specific but an indication of the chronicity of the injury.
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transforming growth factors Beta 1 Beta 2 and Beta 3 messenger rna and protein expression in mouse uterus and vagina during estrogen induced growth a comparison to other estrogen regulated genes
Cell Growth & Differentiation, 1994Co-Authors: Tsuneo Takahashi, K C Flanders, B Eitzman, N L Bossert, D Walmer, K Sparrow, John A Mclachlan, K G NelsonAbstract:Increasing evidence suggests that the differential regulation of multiple peptide growth factors by steroid hormones contributes significantly to the pleiotropic effects elicited in target tissues. We report here an evaluation of the effects of the potent estrogen, diethylstilbestrol, on the expression of the three mammalian transforming growth factor Beta (TGF Beta) isoforms, TGF Beta 1, TGF Beta 2, and TGF Beta 3, in both the uterus and the vagina of the prepubescent mouse. Immunohistochemical protein detection, in situ hybridization, and Northern RNA analyses demonstrate overlapping but distinct time-dependent and site-specific induction of all three TGF Beta genes in the reproductive tract in response to estrogen. Temporal analysis of steady-state levels of the TGF Beta mRNAs in the uterus by Northern blotting clearly demonstrates that diethylstilbestrol significantly but transiently up-regulates TGF Beta 3 mRNA within 30 min and TGF Beta 1 and TGF Beta 2 mRNAs by 3 h with decreases to/or below control levels by 6 h. The vagina also responds to diethylstilbestrol with similar kinetics of induction for TGF Beta 2 and TGF Beta 3 mRNAs as that observed in the uterus; however, TGF Beta 1 mRNA levels increase gradually and peak around 16 h after treatment. Investigation of the steroid specificity demonstrates predominant estrogen specificity in the control of TGF Beta expression in the immature mouse reproductive tract. In situ hybridization localizes the mRNAs for all three TGF Beta isoforms, primarily to the uterine and vaginal epithelium. Unlike the transient nature of TGF Beta mRNA induction elicited by estrogen, immunohistochemistry demonstrates that estrogen treatment results in a more prolonged elevation of the proteins for TGF Beta 1, TGF Beta 2, and TGF Beta 3 in the epithelium of both tissues. Investigation of specific binding of 125I-TGF Beta 1 by affinity labeling reveals the existence of the receptor/binding proteins (types I, II, and III) in the uterus. Estrogen treatment significantly reduces binding to each of these components in the uterus, which suggests that estrogen may modulate TGF Beta responsiveness at the receptor level. A comparison of TGF Beta mRNA expression to the induction of other estrogen-regulated genes, TGF alpha, insulin-like growth factor-1, c-myc, progesterone receptor and lactotransferrin reveals that, in general, the TGF Beta transcript levels are regulated in a more transient manner by estrogen.(ABSTRACT TRUNCATED AT 400 WORDS)
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human uterine tissue throughout the menstrual cycle expresses transforming growth factor Beta 1 TGF Beta 1 TGF Beta 2 TGF Beta 3 and TGF Beta type ii receptor messenger ribonucleic acid and protein and contains 125i TGF Beta 1 binding sites
Endocrinology, 1994Co-Authors: Nasser Chegini, Yong Zhao, R S Williams, K C FlandersAbstract:The use of isoform-specific transforming growth factor-Beta (TGF Beta) primers, 35S-labeled 40-mer oligonucleotide probes and polyclonal antibodies, reverse transcription-polymerase chain reaction, in situ hybridization, and immunohistochemical observations has revealed that human uterine tissue at various reproductive stages expresses TGF Beta s and TGF Beta type II receptor messenger RNAs (mRNAs) and proteins. The reverse transcription-polymerase chain reaction revealed the predicted 443-, 310-, 524-, and 431-basepair fragments for TGF Beta 1, TGF Beta 2, TGF Beta 3, and TGF Beta type II receptor, respectively, in both endometrial and myometrial tissues, which were further verified by restriction enzyme analysis. In situ hybridization and immunohistochemical observations indicated that all uterine cell types express TGF Beta s mRNAs and proteins. In the functionalis region, endometrial luminal and glandular epithelial cells are the primary cell types expressing TGF Beta s mRNAs and proteins, with lesser...
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expression of transforming growth factor Beta isoforms Beta 2 and Beta 3 in the mouse uterus analysis of the periimplantation period and effects of ovarian steroids
Endocrinology, 1992Co-Authors: Sanjoy K Das, K C Flanders, Glen K Andrews, Sudhansu K DeyAbstract:Expression of Beta-type transforming growth factor genes (TGF Beta 2 and TGF Beta 3) in the mouse uterus during the periimplantation period and in response to an acute exposure to 17 Beta-estradiol (E2) and progesterone (P4) was studied using Northern blot hybridization and/or immunocytochemistry. Polyclonal antipeptide antibodies specific for TGF Beta 2 or TGF Beta 3 were employed for immunocytochemistry. In the preimplantation uterus [days (D) 1-4 of pregnancy; day 1 = vaginal plug], immunostaining for TGF Beta 2 was observed in luminal and glandular epithelia as well as in myometrium and vascular smooth muscle. In the postimplantation period (D5-D8), TGF Beta 2 immunostaining was also detected in decidual cells. In contrast, TGF Beta 3 immunostaining was restricted to the myometrium and vascular smooth muscle throughout the periimplantation period (D1-D8). Antisense TGF Beta 2 and TGF Beta 3 RNA probes were employed for Northern blotting. Northern blot hybridization revealed four TGF Beta 2 transcripts...
Hynda K Kleinman - One of the best experts on this subject based on the ideXlab platform.
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role of laminin 1 and TGF Beta 3 in acinar differentiation of a human submandibular gland cell line hsg
Journal of Cell Science, 1996Co-Authors: Matthew P Hoffman, Maura C Kibbey, John J Letterio, Hynda K KleinmanAbstract:Previous studies show that culturing an immortalized human submandibular gland cell line (HSG) on Matrigel, a basement membrane extract, induces cytodifferentiation. We have further defined this model system and identified factors involved in HSG cell acinar development and cyto-differentiation. Acinar development is marked by cell migration into multi-cellular spherical structures, cell proliferation and apoptosis of the centrally localized cells. In addition, functional differentiation was determined by indirect immunofluorescence and immunoblot analysis for cystatin, a salivary gland acinar cell-specific protein found to be produced by differentiated HSG cells. Matrigel contains multiple extracellular matrix proteins, however, laminin-1 was identified as the major matrix component that induced HSG cell acinar development and cytodifferentiation. Antibodies against specific components of Matrigel and against cell surface adhesion molecules were added to cells in culture to identify components important for HSG cell acinar differentiation. Immunostaining of HSG cell acini identified TGF-Beta 2 and Beta 3 as the predominant isoforms within the cells. Neutralizing antibodies directed against TGF-Beta 3 significantly decreased (P
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role of laminin 1 and TGF Beta 3 in acinar differentiation of a human submandibular gland cell line hsg
Journal of Cell Science, 1996Co-Authors: Matthew P Hoffman, Maura C Kibbey, John J Letterio, Hynda K KleinmanAbstract:Previous studies show that culturing an immortalized human submandibular gland cell line (HSG) on Matrigel, a basement membrane extract, induces cytodifferentiation. We have further defined this model system and identified factors involved in HSG cell acinar development and cyto-differentiation. Acinar development is marked by cell migration into multi-cellular spherical structures, cell proliferation and apoptosis of the centrally localized cells. In addition, functional differentiation was determined by indirect immunofluorescence and immunoblot analysis for cystatin, a salivary gland acinar cell-specific protein found to be produced by differentiated HSG cells. Matrigel contains multiple extracellular matrix proteins, however, laminin-1 was identified as the major matrix component that induced HSG cell acinar development and cytodifferentiation. Antibodies against specific components of Matrigel and against cell surface adhesion molecules were added to cells in culture to identify components important for HSG cell acinar differentiation. Immunostaining of HSG cell acini identified TGF-Beta 2 and Beta 3 as the predominant isoforms within the cells. Neutralizing antibodies directed against TGF-Beta 3 significantly decreased (P < or = 0.0002) the size of acini formed. These results indicate that multiple components, including laminin-1 and TGF-Beta 3, contribute to HSG cell acinar development. This model system will be useful to study acinar differentiation and salivary gland-specific protein expression in vitro.
Laurie A Jaeger - One of the best experts on this subject based on the ideXlab platform.
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differential expression of Beta transforming growth factors TGF Beta 1 TGF Beta 2 and TGF Beta 3 and their receptors type i and type ii in peri implantation porcine conceptuses
Biology of Reproduction, 1996Co-Authors: Anupma Gupta, Fuller W Bazer, Laurie A JaegerAbstract:Beta transforming growth factors (TGF Beta 1, TGF Beta 2, and TGF Beta 3) and type I and II TGF Beta receptors were immunohistochemically localized in peri-implantation porcine conceptuses (embryos and associated membranes) collected on Day 10 through Day 14 of gestation. Our results indicate specific immunolocalization of TGF Beta isoforms and their receptors in conceptuses during these gestational days. In parietal endoderm, TGF Beta 1 immunoreactions were weak to undetectable, TGF Beta 2 immunoreactions were intense, and TGF Beta 3 immunoreactions were intermediate in intensity to TGF Beta 2 and TGF Beta 1. In contrast to immunoreactions in endoderm, TGF Beta 1 and TGF Beta 3 immunostaining in trophectoderm (Tr) was intense. Differences in TGF Beta 2 immunostaining of Tr were observed from Days 10 to 14 of gestation. A drastic decrease in cytoplasmic immunostaining of ectoderm and mesoderm was detected from Days 12 to 14 for all TGF Beta isoforms and type II receptor; however, type I receptor immunoreactions were consistently detected between Days 10 and 14. Concurrent expression of both type I and type II receptors in the peri-implantation conceptuses suggests that porcine conceptuses are capable of binding and responding to TGF Beta s during this period. Differential expression of the three TGF Beta isoforms suggests different roles for TGF Beta s 1, 2, and 3 in conceptus development. Our results suggest possible roles for TGF Beta s in early growth and differentiation of the embryo, differentiation of the Tr, and implantation.
Leslie I Gold - One of the best experts on this subject based on the ideXlab platform.
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increased levels of transforming growth factor Beta in hiv associated nephropathy
Kidney International, 1999Co-Authors: Tatsuo Yamamoto, Leslie I Gold, Nancy A Noble, Diane E Miller, Akira Hishida, Mitsumasa Nagase, Arthur H Cohen, Wayne A BorderAbstract:BACKGROUND Human immunodeficiency virus-associated nephropathy (HIVAN) is a renal disease of unknown pathogenesis. Recent evidence suggests that the fibrogenic cytokine transforming growth factor-Beta (TGF-Beta) might be involved. We hypothesized that overproduction of TGF-Beta in the kidney might be involved in the pathogenesis of HIVAN. METHODS The mRNA and protein expression of TGF-Beta isoforms, TGF-Beta 1, TGF-Beta 2, and TGF Beta 3, deposition of matrix proteins induced by TGF-Beta, and levels of HIV Tat protein were studied in HIVAN. Controls included normal and diseased kidneys from HIV-positive and -negative patients. The ability of Tat to induce production of TGF-Beta and matrix proteins was also studied in human mesangial cells. RESULTS Normal kidneys, thin basement membrane nephropathy, and minimal change disease were negative for the three TGF-Beta isoforms and Tat. In HIVAN, levels of TGF-Beta isoforms and Tat were significantly increased, along with the expression of TGF-Beta mRNA and deposition of matrix proteins stimulated by TGF-Beta. Increased levels of TGF-Beta isoforms, but not Tat, were also found in other glomerular diseases characterized by matrix accumulation. HIV infection, in the absence of HIVAN, was not associated with an increase in TGF-Beta or Tat expression. Tat stimulated the expression and production of TGF-Beta 1 and matrix proteins by human mesangial cells. CONCLUSIONS Our findings suggest that overproduction of TGF-Beta is involved in the pathogenesis of HIVAN.
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increased expression of transforming growth factor β isoforms and basic fibroblast growth factor in complex hyperplasia and adenocarcinoma of the endometrium evidence for paracrine and autocrine action
Cancer Research, 1994Co-Authors: Leslie I Gold, Babita Saxena, Khush Mittal, Michael Marmor, Sunanda Goswami, Lila Nactigal, Murray Korc, Rita I DemopoulosAbstract:Endometrial carcinoma is associated with antecedent simple and complex hyperplasia, and the endometrium is a target tissue for the action of cytokines and growth factors. Transforming growth factor (TGF)-Beta s are potent cellular growth and differentiation regulatory factors. Therefore, we investigated the potential role for TGF-Beta s in the normal proliferative endometrium and its possible involvement in the transition to complex hyperplasia and progression to endometrial carcinoma. The angiogenic and mitogenic growth factor, basic fibroblast growth factor, was used for comparison. Differential TGF-Beta isoform-specific immunoreactivity was observed in the normal endometrium, which is composed of glandular and stromal cells. There was an increase in TGF-Beta 3 but not TGF-Beta 1 or TGF-Beta 2 in the glandular epithelium from the proliferative to the secretory phase of the menstrual cycle. Immunostaining for TGF-Beta 2 was more intense in the stroma than the glands. In contrast, TGF-Beta 1 and TGF-Beta 3 were near equal intensity in these two endometrial compartments, TGF-Beta 3 being the most intense. The glandular epithelium demonstrated a statistically significant stepwise increase in the expression of all three TGF-Beta s progressing from the normal proliferative endometrium to simple hyperplasia and on to complex hyperplasia. However, the stromal cells maintained approximately the same level of immunoreactivity for TGF-Beta in all these samples. In comparing proliferative endometrium with complex hyperplasia, there was a 5.1-, 3.4-, and 2.6-fold increase in immunostaining in the glands for TGF-Beta 1, TGF-Beta 2, and TGF-Beta 3, respectively (P < or = 0.001). There was no further increase in immunoreactivity with progression from preneoplastic complex hyperplasia to carcinoma. Immunoreactive basic fibroblast growth factor was slight in normal endometrium and simple hyperplasia. There was a 4.6- and 4.2-fold increase in immunostaining observed in complex hyperplasia compared with proliferative endometrium in the glandular (P < or = 0.0054) and stromal (P < or = 0.0053) cells, respectively, with no further increase in carcinoma. By in situ hybridization, an increase in mRNA for all TGF-Beta isoforms paralleled TGF-Beta immunoreactivity. However, in contrast to the increased immunostaining in the glands in complex hyperplasia, there was remarkably more mRNA in the stromal cell compartment. The discordant expression of mRNA and protein was only observed in the pathological endometrium since both were more highly expressed in the stromal cells in normal proliferative endometrium.(ABSTRACT TRUNCATED AT 400 WORDS)
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inhibition of mammary duct development but not alveolar outgrowth during pregnancy in transgenic mice expressing active TGF Beta 1
Genes & Development, 1993Co-Authors: D F Pierce, Leslie I Gold, Brigid L M Hogan, Mahlon D Johnson, Yasuhisa Matsui, S D Robinson, A F Purchio, C W Daniel, Harold L MosesAbstract:The transforming growth factors Beta (TGFs-Beta) are potent inhibitors of cell proliferation and are usually secreted in a latent form. TGF-Beta 1, TGF-Beta 2, and TGF-Beta 3 are expressed in distinct but overlapping patterns in the developing mouse mammary gland. To study the role of transforming growth factor-Beta 1 (TGF-Beta 1) in normal mammary development and in mammary neoplasia, we have constructed three transgenic mouse lines that express a simian TGF-Beta 1 s223/225 mutated to produce a constitutively active product under the control of the MMTV enhancer/promoter. Expression of the transgene, as confirmed by in situ hybridization, immunohistochemistry, and Northern blot analysis, was associated with marked suppression of the normal pattern of mammary ductal tree development in female transgenics. Reduction in total ductal tree volume was observed at 7 weeks, soon after estrous begins, and was most apparent at 13 weeks, as ductal growth in the normal mammary gland declines. This effect was seen in all three lines. However, during pregnancy, alveolar outgrowths developed from the hypoplastic ductal tree, and lactation occurred, therefore, all transgenic females could feed full litters. Unlike many other transgenic mouse models in which expression of growth factors or oncogenes under control of the MMTV promoter leads to mammary epithelial hyperplasia and increased tumor formation, the MMTV-TGF-Beta 1S223/225 transgene causes conditional hypoplasia of the mammary ductal tree and no spontaneous tumors have been detected in the MMTV-TGF-Beta 1S223/225 transgenic animals.
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spatial and temporal patterns of immunoreactive transforming growth factor Beta 1 Beta 2 and Beta 3 during excisional wound repair
American Journal of Pathology, 1993Co-Authors: J H Levine, Harold L Moses, Leslie I Gold, Lillian B NanneyAbstract:Transforming growth factor Beta (TGF-Beta) regulates cellular growth and differentiation and stimulates the synthesis and secretion of protein constituents of the extracellular matrix. Three isoforms of TGF-Beta have been found in mammals. Although the biological activities of TGF-Beta 1, TGF-Beta 2, and TGF-Beta 3 are similar at the level of cell culture, distinct in vivo functions for these molecules are emerging. To gain insight into the role of each isoform in wound repair, antibodies specific for each isoform of TGF-Beta were used to examine excisional wound repair. Marked differences in the temporal and spatial relationships for immunoreactive TGF-Beta 1, -Beta 2, and -Beta 3 were noted throughout the repair process. TGF-Beta 2 and TGF-Beta 3 were prevalent by 24 hours after excisional wounding, and strong immunoreactivity was observed in the migrating epidermis. Subtle changes in immunoreactivity occurred for TGF-Beta 2 and TGF-Beta 3 in cells of the epidermal appendages, mesenchymal derivatives, granulation tissue, and the underlying dermis throughout wound repair. In contrast, TGF-Beta 1 was not associated with any undifferentiated cells and was not present in the dermis and most dermal structures in both nonwounded skin or wounds until day 5 after wounding, when re-epithelialization was complete. Following re-epithelialization, TGF-Beta 2 and TGF-Beta 3 were present in all four layers of stratum corneum of the differentiating epidermis. All three TGF-Beta isoforms were present in mesenchymal cells and basal lamina, suggesting their role in the modulation of dermal-epidermal interaction during wound repair. Our observations support individual in vivo function for TGF-Beta isoforms in cutaneous wound repair.
Matthew P Hoffman - One of the best experts on this subject based on the ideXlab platform.
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role of laminin 1 and TGF Beta 3 in acinar differentiation of a human submandibular gland cell line hsg
Journal of Cell Science, 1996Co-Authors: Matthew P Hoffman, Maura C Kibbey, John J Letterio, Hynda K KleinmanAbstract:Previous studies show that culturing an immortalized human submandibular gland cell line (HSG) on Matrigel, a basement membrane extract, induces cytodifferentiation. We have further defined this model system and identified factors involved in HSG cell acinar development and cyto-differentiation. Acinar development is marked by cell migration into multi-cellular spherical structures, cell proliferation and apoptosis of the centrally localized cells. In addition, functional differentiation was determined by indirect immunofluorescence and immunoblot analysis for cystatin, a salivary gland acinar cell-specific protein found to be produced by differentiated HSG cells. Matrigel contains multiple extracellular matrix proteins, however, laminin-1 was identified as the major matrix component that induced HSG cell acinar development and cytodifferentiation. Antibodies against specific components of Matrigel and against cell surface adhesion molecules were added to cells in culture to identify components important for HSG cell acinar differentiation. Immunostaining of HSG cell acini identified TGF-Beta 2 and Beta 3 as the predominant isoforms within the cells. Neutralizing antibodies directed against TGF-Beta 3 significantly decreased (P
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role of laminin 1 and TGF Beta 3 in acinar differentiation of a human submandibular gland cell line hsg
Journal of Cell Science, 1996Co-Authors: Matthew P Hoffman, Maura C Kibbey, John J Letterio, Hynda K KleinmanAbstract:Previous studies show that culturing an immortalized human submandibular gland cell line (HSG) on Matrigel, a basement membrane extract, induces cytodifferentiation. We have further defined this model system and identified factors involved in HSG cell acinar development and cyto-differentiation. Acinar development is marked by cell migration into multi-cellular spherical structures, cell proliferation and apoptosis of the centrally localized cells. In addition, functional differentiation was determined by indirect immunofluorescence and immunoblot analysis for cystatin, a salivary gland acinar cell-specific protein found to be produced by differentiated HSG cells. Matrigel contains multiple extracellular matrix proteins, however, laminin-1 was identified as the major matrix component that induced HSG cell acinar development and cytodifferentiation. Antibodies against specific components of Matrigel and against cell surface adhesion molecules were added to cells in culture to identify components important for HSG cell acinar differentiation. Immunostaining of HSG cell acini identified TGF-Beta 2 and Beta 3 as the predominant isoforms within the cells. Neutralizing antibodies directed against TGF-Beta 3 significantly decreased (P < or = 0.0002) the size of acini formed. These results indicate that multiple components, including laminin-1 and TGF-Beta 3, contribute to HSG cell acinar development. This model system will be useful to study acinar differentiation and salivary gland-specific protein expression in vitro.