Possible role of transforming growth factor-beta in relapsing-remitting multiple sclerosis

Cerebrospinal fluid (CSF) and serum levels of transforming growth factor (TGF)-beta and soluble intercellular adhesion molecule-1 (sICAM-1) were evaluated in ten patients with definite multiple sclerosis (MS) of the relapsing-remitting type. CSF TGF-beta levels of MS patients in remission were significantly (p < 0.01) higher than of MS patients in active phase, and there was a significant inverse correlation (p < 0.05) between TGF-beta and slCAM-1 levels in the CSF of patients in both remitting and relapsing type. This is consistent with a possible down-regulation of TGF-beta on ICAM-1 expression and suggests a possible synthesis in the central nervous system of TGF-beta.     

A critical role for transforming growth factor-beta in donor transfusion-induced allograft tolerance

To evaluate the relationship between carotenoid concentrations in serum and breast tissue, we measured serum carotenoid concentrations and endogenous carotenoid levels in breast adipose tissue of women with benign breast tumor (n = 46) or breast cancer (n = 44). Before extraction, serum was digested with lipase and cholesterol esterase, and breast adipose tissue was saponified. Serum and tissue carotenoids were extracted with ether/hexane and measured by using HPLC with a C30 column. Serum retinoic acid was extracted with chloroform/methanol and measured using HPLC with a C18 column. There were no significant differences in serum carotenoids [lutein, zeaxanthin, cryptoxanthin (both alpha- and beta-), alpha-carotene, all-trans beta-carotene, 13-cis beta-carotene and lycopene], retinoids (retinol, all-trans and 13-cis retinoic acids), and alpha- and gamma- tocopherol concentrations between benign breast tumor patients and breast cancer patients. A substantial amount of 9-cis beta-carotene was present in adipose tissue and was the only carotenoid that had a significantly lower level in benign breast tumor patients than in breast cancer patients. Correlations between carotenoid concentrations in serum and in breast adipose tissue were determined by combining the data of the two groups. Concentrations of the major serum carotenoids except cryptoxanthin showed significant correlations with breast adipose tissue carotenoid levels. When the concentrations of serum carotenoids were adjusted for serum triglycerides or LDL, correlations between serum carotenoid concentrations and breast adipose tissue carotenoid levels markedly increased, including that of cryptoxanthin (P <0. 001). The strong correlation between serum carotenoid concentrations and endogenous breast adipose tissue carotenoid levels indicate that dietary intake influences adipose tissue carotenoid levels as well as serum concentrations, and that adipose tissue is a dynamic reservoir of fat-soluble nutrients.     

Latent transforming growth factor-beta binding protein domains involved in activation and transglutaminase-dependent cross-linking of latent transforming growth factor-beta

Transforming growth factor-beta (TGF-beta) is secreted by many cell types as part of a large latent complex composed of three subunits: TGF-beta, the TGF-beta propeptide, and the latent TGF-beta binding protein (LTBP). To interact with its cell surface receptors, TGF-beta must be released from the latent complex by disrupting noncovalent interactions between mature TGF-beta and its propeptide. Previously, we identified LTBP-1 and transglutaminase, a cross-linking enzyme, as reactants involved in the formation of TGF-beta. In this study, we demonstrate that LTBP-1 and large latent complex are substrates for transglutaminase. Furthermore, we show that the covalent association between LTBP-1 and the extracellular matrix is transglutaminase dependent, as little LTBP-1 is recovered from matrix digests prepared from cultures treated with transglutaminase inhibitors. Three polyclonal antisera to glutathione S-transferase fusion proteins containing amino, middle, or carboxyl regions of LTBP-1S were used to identify domains of LTBP-1 involved in cross-linking and formation of TGF-beta by transglutaminase. Antibodies to the amino and carboxyl regions of LTBP-1S abrogate TGF-beta generation by vascular cell cocultures or macrophages. However, only antibodies to the amino-terminal region of LTBP-1 block transglutaminase-dependent cross-linking of large latent complex or LTBP-1. To further identify transglutaminase-reactive domains within the amino-terminal region of LTBP-1S, mutants of LTBP-1S with deletions of either the amino-terminal 293 (deltaN293) or 441 (deltaN441) amino acids were expressed transiently in CHO cells. Analysis of the LTBP-1S content in matrices of transfected CHO cultures revealed that deltaN293 LTBP-1S was matrix associated via a transglutaminase-dependent reaction, whereas deltaN441 LTBP-1S was not. This suggests that residues 294-441 are critical to the transglutaminase reactivity of LTBP-1S.     

Retinoids potentiate transforming growth factor-beta activity in bovine endothelial cells through up-regulating the expression of transforming growth factor-beta receptors

The present paper reports data on secular trends in the stature of Brazilian Navy recruits born from 1940 to 1965. The final sample included 3269 individuals aged 18.00-18.99. Statistics performed were: ANOVA (one-way and two-way), Sheffe test, simple linear regression between stature and year of birth, and multiple linear regression adjusting for level of schooling (beta coefficient) and chi-square. Results indicated a progressive growth trend in stature of 0.1 cm/yr. for the country as a whole. The trend was also observed for nearly all regions and two out of three levels of schooling and can be explained by improvement in some of the country's health indicators. One important characteristic was a higher level of schooling observed among Navy recruits, suggesting that these individuals represent a highly select group, and that therefore data on the Navy cannot be applied directly to the Brazilian population as a whole.     

Immunolocalization of transforming growth factor-beta 1 and transforming growth factor-beta 2 in the mouse ovary during gonadotrophin-induced follicular maturation

An immunohistochemical approach was utilized to evaluate the cellular distribution of transforming growth factor-beta 1 (TGF beta 1) and transforming growth factor beta 2 (TGF beta 2) at different stages of follicle development in the prepubertal mouse ovary under the following conditions: (i) after pregnant mare's serum gonadotrophin (PMSG) treatment; (ii) after PMSG and human chorionic gonadotrophin (HCG) treatment; (iii) after PMSG and HCG treatment plus mating. In the immature ovary, TGF beta 1 and TGF beta 2 immunoreactivities are localized in theca and granulosa cells and in oocytes. After PMSG treatment, TGF beta 1 and TGF beta 2 immunoreactivities are localized in granulosa cells; in addition, TGF beta 2 staining is noted in the matrix surrounding antral cells. Staining for both TGR beta 1 and TGF beta 2 drops in the theca but persists in the oocyte. PMSG plus HCG treatment results in a significant increase in TGF beta 1 and TGF beta 2 immunoreactivity in the theca and in the maintenance of TGF beta 1 staining in both basal granulosa cells and cumulus cells whereas TGF beta 2 immunoreactivity is essentially localized in the matrix surrounding cumulus cells. Staining for TGF beta 1 and TGF beta 2 persists in the oocyte. Following PMSG plus HCG treatment and mating, TGF beta 1 immunoreactivity is localized in the luteal cells of corpora lutea and TGF beta 2 shows a similar localization pattern. This study provides evidence that TGF beta 1 and TGF beta 2 peptides are expressed in specific cell types during induced follicular maturation in the mouse ovary.     

Molecular mechanisms of transforming growth factor-beta signaling

The present experiments examined the effects of posttraining intrahippocampal injections of the degradative enzyme-resistant methylcarbamyl analog of the bioactive phospholipid platelet-activating factor (mc-PAF) and the platelet-activating factor (PAF) receptor antagonists BN52021 and BN 50730 on memory in male Long-Evans rats trained in a hidden platform version of the Morris water maze. Following an eight-trial training session, rats received a unilateral intrahippocampal injection of mc-PAF (0.5, 1.0, or 2.0 microgram/0.5 microliter), lyso-PAF (1.0 microgram/0.5 microliter), the cell surface PAF receptor antagonist BN 52021 (0.25, 0.5, or 1.0 micrigram/0.5 microliter/, the intracellular PAF receptor antagonist BN 50730 (2.0, 5.0, or 10.0 microgram/0.5 microliter), or vehicle (50% DMSO in 0.9% saline; 0.5 microliter). On a retention test conducted 24 h after training, the escape latencies of rats administered mc-PAF (1.0 or 2.0 microgram) were significantly lower than those of the vehicle-injected controls, demonstrating a memory-enhancing effect of mc-PAF. Injections of lyso-PAF, a structurally similar metabolite of PAF, had no influence on memory, indicating that the memory-enhancing effect of mc-PAF is not caused by membrane perturbation by the phospholipid. The retention test escape latencies of rats administered BN 52021 (0.5 microgram) and BN 50730 (5.0 or 10 microgram) were significantly higher than those of the controls, indicating a memory impairing effect of both PAF antagonists. When mc-PAF, BN 52021, or BN 50730 was administered 2 h posttraining, no effect on retention was observed, indicating a time-dependent effect of the neuroactive substances on memory storage. The findings suggest a role for endogenous PAF in hippocampal-dependent memory processes.     

Mandibular reconstruction with transforming growth factor-beta1

This is a case report of a 43-year-old woman who received a transplant for end-stage liver disease due to hereditary hemorrhagic telangiectasia and fibropolycystic liver disease. This is an uncommon association of two autosomal-dominant conditions with defined genetic and molecular defects. The liver showed extensive vascular malformations of arteries and veins as well as telangiectasia and fibrosis. In addition, there were cystically dilated ducts containing inspissated bile and extensive von Meyenburg complexes. This case raises interesting questions about the possible relationship of these genes and their gene products, both of which are related to cell-matrix interactions and are strongly associated with blood vessels, one of them being expressed on endothelial cells and the other being developmentally important in blood vessels.     

Functions of the transforming growth factor-beta superfamily in eyes

One human body is composed of 6 x 10(13) cells, and eyes are also composed of many cells of different functions. The cellular functions and intercellular interaction are regulated by many regulators including cytokines and growth factors to maintain the homeostasis. The transforming growth factor-beta (TGF-beta) superfamily, a large family of multifunctional factors, regulates various cellular functions, including cellular proliferation, migration, differentiation, apoptosis and extracellular matrix production. The TGF-beta superfamily contains about 30 multifunctional factors, and is divided into several families according to the sequence homology. The TGF-beta family, the activin family, and bone morphogenic proteins belong to the TGF-beta superfamily. TGF-beta superfamily members transduce signals through type I and type II serine/threonine type transmembrane receptors. The signals are transduced from receptors through nuclei by Smad family members, which are phosphorylated by the activated type I receptors and translocate from cytoplasm into nuclei. TGF-beta family members and the TGF-beta superfamily receptor family are expressed in ocular tissues including the cornea, ciliary epithelium, lens epithelium, retina, and blood vessels. This observation suggests the importance of the TGF-beta superfamily in eyes. Smad family members (Smad 1, Smad 2, Smad 3 and Smad 4) are expressed in the cultured retinal pigmant epithelial cell line (D407), in which TGF-beta and activin A stimulate the translocation of Smad 2, but not Smad 1 into nuclei, whereas bone morphogenetic protein (BMP) stimulates that of Smad 1, but not Smad 2. TGF-beta superfamily members play important roles in the pathogenesis of retinal neovascularization and in the wound healing process of corneal tissue. TGF-beta inhibits the endothelial functions, but, stimulates angiogenesis in vivo. TGF-beta is involved in the formation of abnormal connective tissue in corneal wound healing. In these processes, many cytokines and growth factors are involved, interacting with each other and forming networks. It is mandatory to clarify the networks to investigate molecular pathogenesis and new therapeutic agents.     

Cataract induction in lenses cultured with transforming growth factor-beta

PURPOSE: Anterior subcapsular cataracts are characterized by the appearance of opaque plaques of abnormal cells. Distinctive spindle-shaped cells containing alpha-smooth muscle actin are present and are associated with wrinkling of the overlying lens capsule. Accumulations of extracellular matrix, including type I collagen, also are found. The authors previously reported that transforming growth factor-beta (TGF-beta) induces similar aberrant morphologic changes in lens epithelial explants. More recently, they identified alpha-smooth muscle actin in explants cultured with TGF-beta. The aim of this study was to determine whether TGF-beta induces comparable cataractous changes in whole lenses and to examine the effects of this treatment on the transparency of the lens. METHODS: Whole lenses from 21-day-old rats were cultured in defined serum-free medium with TGF-beta 2 or without added growth factors for 5 days. Lenses were then photographed and prepared for histology and immunolocalization. RESULTS: Lenses cultured with TGF-beta developed distinct anterior opacities just beneath the lens capsule. Histologically, clumps of abnormal cells corresponded with these opacities. Spindle-shaped cells, which contained alpha-smooth muscle actin, were present, and the overlying capsule was often wrinkled. The clumps contained accumulations of type I collagen, laminin, and heparan sulphate proteoglycan. In contrast, lenses cultured without growth factors remained transparent, retained normal lens morphology, and did not accumulate alpha-smooth muscle actin or type I collagen. CONCLUSIONS: These results show that TGF-beta induces whole lenses to form opacities that contain morphologic and biochemical markers for subcapsular cataract.     

A role of the transforming growth factor-beta in suppression of B-cell blastogenesis mediated by erythroid cells

The bio-psycho-social model was used in the presented study to observe the course of chronic diseases. An attempt was undertaken to correlate the psychosocial situation of 165 women with no presence of disease following breast cancer or genital cancer with their present organic status. The open discussion, a half standardized interview and the gynecological-oncological physical examination were implemented using predetermined parameters. The results of the general well-being scores from the interview and the results of organic status for all 165 patients were related using a rank-correlation between the objective and subjective score. A discrepancy between the psychosocial situation and the objective physical finding was found in the majority of women. The goal of the treatment of chronically ill patients especially following oncological tumors should thus have equal emphasis on the psychosocial and organic dimensions of the disease.     

Synthesis and expression of transforming growth factor-beta in activated macrophages

It has been established that once macrophages become activated, they pass through different stages of functional activity. Mouse macrophages activated by BCG "exerted" pronounced cytotoxic effects for 2-5 days to be followed later by growth-stimulating ones. However, in other experiments, the cytotoxic effect was either absent or occurred at later stages which was probably due to a certain functional state of macrophages before activation. The synthesis of TGF-beta increased 1-2 days after activation with BCG vaccine, lipopolysacharide and gamma radiation. An increase in mRNA TGF-beta i expression was observed only 5 days after activation of macrophages.     

Amyloid beta-peptide possesses a transforming growth factor-beta activity

Amyloid beta-peptide (Abeta) of 39-42 amino acid residues is a major constituent of Alzheimer's disease neurite plaques. Abeta aggregates (fibrils) are believed to be responsible for neuronal damage and dysfunction, as well as microglia and astrocyte activation in disease lesions by multiple mechanisms. Since Abeta aggregates possess the multiple valencies of an FAED motif (20th to 23rd amino acid residues), which resembles the putative transforming growth factor-beta (TGF-beta) active site motif, we hypothesize that Abeta monomers and Abeta aggregates may function as TGF-beta antagonists and partial agonists, analogous to previously described monovalent and multivalent TGF-beta peptide antagonists and agonists (Huang, S. S., Liu, Q., Johnson, F. E., Konish, Y., and Huang, J. S. (1997) J. Biol. Chem. 272, 27155-27159). Here, we report that the Abeta monomer, Abeta-(1-40) and its fragment, containing the motif inhibit radiolabeled TGF-beta binding to cell-surface TGF-beta receptors in mink lung epithelial cells (Mv1Lu cells). Abeta-(1-40)-bovine serum albumin conjugate (Abeta-(1-40)-BSA), a multivalent synthetic analogue of Abeta aggregates, exhibited cytotoxicity toward bovine cerebral endothelial cells and rat post-mitotic differentiated hippocampal neuronal cells (H19-7 cells) and inhibitory activities of radiolabeled TGF-beta binding to TGF-beta receptors and TGF-beta-induced plasminogen activator inhibitor-1 expression, that were approximately 100-670 times more potent than those of Abeta-(1-40) monomers. At less than micromolar concentrations, Abeta-(1-40)-BSA but not Abeta-(1-40) monomers inhibited proliferation of Mv1Lu cells. Since TGF-beta is an organizer of responses to neurodegeneration and is also found in neurite plaques, the TGF-beta antagonist and partial agonist activities of Abeta monomers and aggregates may play an important role in the pathogenesis of the disease.     

Effect of ionizing radiation on transforming growth factor-beta expression

We report on papers concerning in topic "Diseases of the breast", which were published in the Zentralblatt für Gyn?kologie during the first half of the 20th century. Only 26 publications about senologic problems were found in 44 years. Papers about the mammary theory of eclampsia, mastitis, plastic operations and breast cancer are reported.     

Distribution of transforming growth factor-beta isoforms in the mammalian retina

The distribution of transforming growth factor-beta (TGF-beta) was examined in the posterior segment of the monkey, human, and feline eye using antisera to TGF-beta 1, TGF-beta 2, or TGF-beta 3. A number of different antibodies, tissue processing methods, immunolocalization techniques, and microscopic imaging systems were used in an attempt to gain a more comprehensive picture of TGF-beta isoform distribution in the retina and retinal pigmented epithelium (RPE). The results are generally consistent in identifying one or more of the three TGF-beta isoforms in the cytoplasm of a small, overlapping subset of cells. RPE cells, photoreceptors, Mueller cells, ganglion cells, hyalocytes, and cells associated with choroidal and retinal vessels are all represented in this immunoreactive population. No evidence of extracellular labeling was noted. The intracellular distribution of the three isoforms is distinctly different in photoreceptors. Anti-TGF-beta 1 precursor and anti-TGF-beta 2 immunoreactivity is confined primarily to rod outer segments, whereas anti-TGF-beta 3 immunoreactivities are restricted to mitochondria within inner segments. In the RPE, clusters of anti-TGF-beta 2 positive cytoplasmic granules are located near the cells' lateral borders, whereas anti-TGF-beta 3 labeling is concentrated apically. These results provide baseline information from which new hypotheses regarding the function(s) of TGF-beta isoforms in the retina can be formulated.     

Modulation of transforming growth factor-beta 1 effects by cytokines

The purpose of the present study was to determine the effects of human recombinant transforming growth factor-beta 1 (TGF-beta 1) on the proliferation of normal cell and cancer cell lines and to evaluate the mechanism of TGF-beta-induced immunosuppression. Murine H238 fibrosarcoma and human UC-11 glioblastoma cells showed no proliferative change in the presence of TGF-beta, whereas the growth of human LS174T colon adenocarcinoma cells was significantly enhanced at the lower concentrations of TGF-beta. In contrast, Mono/Mac-6, a human monocyte cell line, human peripheral blood mononuclear (PBMN) cells, and BALB/c mouse spleen cells were significantly suppressed by 2.5 to 250 ng/ml of TGF-beta. In order to investigate the mode of action, TGF-beta and other cytokines were added 0, 1, and 2 days after initiation of the culture. Mono/Mac-6 cells showed that 2 days are needed for TGF-beta-induced suppression. Simultaneous addition of TGF-beta and tumor necrosis-alpha (TNF-alpha; 600 units/ml) to Mono/Mac-6 cells resulted in nearly complete suppression by day 3. IL-2, and to a lesser extent IL-4, was able to counteract the suppressive effects of TGF-beta on mitogen-stimulated spleen cells. However, our results indicate that IL-2 is not as effective in restoring responsiveness once T cell activation is well underway. IL-1 and interferon-gamma had no effects on TGF-beta-mediated immunosuppression. Since TGF-beta depressed normal cell growth and since IL-2 could effectively counteract the suppression, we assayed for IL-2 production. When normal spleen cells were treated with 2.5 ng of TGF-beta/ml, a 3.4-fold decrease in IL-2 production was observed. This is a potential mechanism for TGF-beta-mediated immunosuppression.     

Role of transforming growth factor-beta in long-term synaptic facilitation in Aplysia

The role of transforming growth factor-beta (TGF-beta) in long-term synaptic facilitation was examined in isolated Aplysia ganglia. Treatment with TGF-beta1 induced long-term facilitation (24 and 48 hours), but not short-term (5 to 15 minutes) or intermediate-term (2 to 4 hours) facilitation. The long-term effects of TGF-beta1 were not additive with those of serotonin. Moreover, serotonin-induced facilitation was blocked by an inhibitor of TGF-beta. Thus, activation of TGF-beta may be part of the cascade of events underlying long-term sensitization, consistent with the hypothesis that signaling molecules that participate in development also have roles in adult neuronal plasticity.     

Involvement of IFN-gamma and transforming growth factor-beta in graft-vs-host reaction-associated immunosuppression

The mechanisms of the suppressive activity of spleen cells from mice undergoing a graft-vs-host reaction (GVH) to non-H-2 histocompatibility Ag were investigated. In our model GVH is induced by injecting bone marrow and spleen cells from B10.D2 (H-2d Mlsb) donors into lethally irradiated (DBA/2 x B10.D2)F1 (H-2d/d Mlsa/b) recipients that differ only with regard to non-H-2 Ag. GVH spleen cells inhibit the mitogenic responses to Con A and LPS, as well as the anti-bromelain-treated mouse RBC (Br-MRBC) antibody response. This suppression was nonspecific and non-H-2-restricted and was not modified after treatment with anti-Thy-1 plus C. Conversely it was abrogated after treatment with L-leucyl methyl ester. These features permitted the identification of non-T cell, L-leucyl methyl ester-sensitive, cells involved in this type of suppression. The suppression mediated by GVH spleen cells was linked to the activity of IFN-gamma and transforming growth factor-beta 1 (TGF-beta 1) (TGF-beta 1 was found to be synthesized by GVH spleen T cells). mAb to IFN-gamma abrogated the suppression of the mitogenic response to Con A and the anti-Br-MRBC response and slightly reversed the suppression of the mitogenic response to LPS. Anti-TGF-beta 1 antibody partially abrogated the suppression of the mitogenic response to LPS and totally abrogated that of the anti-Br-MRBC response but left unmodified the suppression of the mitogenic response to Con A. These results are discussed within the framework of the mechanisms underlying the immunosuppression associated with GVH.     

Altered expression of transforming growth factor-beta S in chronic renal rejection

We examined the altered expression of transforming growth factor-beta s in chronic renal rejection in humans, including transforming growth factor beta-1 (TGF-beta 1), TGF-beta 2, TGF-beta 3 and their receptors, transforming growth factor beta receptor type I (T beta R-I) and T beta R-II. Using Northern blot analysis and immunohistochemistry, 10 specimens of chronically rejected and 8 normal kidney samples were analyzed. By Northern blot analysis the expression of mRNA encoding TGF-beta 1, TGF-beta 2, TGF-beta 3 (P < 0.02), T beta R-I and T beta R-II (P < 0.02) was decreased in chronically rejected renal cortex samples, compared to normal controls. Immunohistochemical analysis of the normal renal cortex showed strong immunostaining for TGF-beta 1 and TGF-beta 3, and mild immunostaining for TGF-beta 2 in the proximal and distal tubulointerstitium, but no signal for any of the TGF-beta isoforms in the glomeruli or in the cortical vessels. In sharp contrast, the glomeruli and the cortical vessels of the rejected kidney specimens exhibited strong immunostaining for TGF-beta 1 and TGF-beta 3, whereas the tubules revealed a decrease in immunoreactivity. T beta RI and T beta RII immunostaining showed similar changes as observed with TGF-beta 1 and TGF-beta 3 antibodies. There was a concomitant increase in B-cell accumulation in the glomeruli, while T-cells and macrophages were diffusely abundant in the rejected samples. Since TGF-beta S are potent inducers of extracellular matrix proteins and have been shown to be involved in fibrotic disease, the increase in TGF-beta 1 and TGF-beta 3 immunoreactivity in the glomeruli suggests that there is a redistribution in TGF-beta expression in chronic renal allograft rejection. Together with changes affected by B-cell mediated immunity, the above alterations might contribute to the histopathological changes that occur in this disorder, such as intimal fibrosis, arteriosclerosis and glomerular and tubular sclerosis.