Biomedical subjects

K C Flanders

Publications and source records attributed to K C Flanders.

At least 73 records · Page 4Linked to original sources

PubMed1993

Association of transforming growth factor-beta 1 with prostate cancer: an immunohistochemical study.

Prostate tissue samples from patients with prostatic carcinoma (PC) and/or benign prostatic hyperplasia (BPH) were examined for expression of transforming growth factor-beta 1 (TGF-beta 1) using an immunohistochemical technique. Tissues were stained with CC and LC antisera, which react with extracellular and intracellular TGF-beta 1, respectively. All PC and BPH tissues showed positive extracellular staining; however, CC-immunoreactive material was significantly more extensive in PC compared with BPH, the average positively staining areas being 59% and 26%, respectively. This differential staining pattern was evident in cases in which areas of PC were located adjacent to areas of BPH. LC staining was identified exclusively intracellularly involving both stromal and epithelial cells in cases of PC as well as BPH. However, while stromal cell staining was more pronounced in BPH, epithelial cell staining tended to be more extensive and more intense in PC. The findings suggest that TGF-beta 1 may be biologically important in the development of PC and BPH.

Adenocarcinoma↗

PubMed1993

TGF-beta expression in the human colon: differential immunostaining along crypt epithelium.

Samples of colorectal carcinoma, adenoma and normal colorectal mucosa were examined for the expression of TGF-beta by immunohistochemistry. Immunoreactivity for TGF-beta was present in 52 out of a total of 58 samples of normal mucosa examined. In adenomas and carcinomas TGF-beta expression was observed in eight out of ten and 46 out of 48 samples respectively and was largely restricted to epithelial cells. In normal mucosa differential expression of TGF-beta was present within epithelial cells, those in the upper parts of the crypts showing enhanced immunoreactivity compared to cells in the proliferative compartment. This pattern of differential staining is consistent with TGF-beta having an important role in the control of growth and differentiation in colonic mucosa.

Adenoma↗

PubMed1993

Hyperthermia induces expression of transforming growth factor-beta s in rat cardiac cells in vitro and in vivo.

Hyperthermia causes changes in expression of TGF-beta mRNA and protein in cultured cardiac cells, as well as in the heart in vivo. 12 h after hyperthermia, primary cultures of neonatal rat cardiomyocytes show a two- to threefold decreased expression of TGF-beta mRNAs which returns to control levels by 48 h after heat shock. In cultures of cardiac fibroblasts, expression of TGF-beta mRNAs increases 5-25-fold, 12-48 h after heat shock, while fetal bovine heart endothelial cells show little change in TGF-beta expression after hyperthermia. In each case, mRNAs for TGF-beta s 1, 2, and 3 are regulated similarly. Hearts isolated from rats exposed to hyperthermia show an initial 20-fold decrease in TGF-beta 1 and 3 mRNA levels which return to control levels by 24 h and subsequently are elevated two- to threefold above normal 48-72 h after heat shock; there is little change in TGF-beta 2 mRNA. Expression of immunoreactive TGF-beta 1 and 3 protein, localized intracellularly in myocytes, follows the same pattern as the mRNA expression. By 72 h, some myocytes show hyperstaining for TGF-beta 1. Staining for extracellular TGF-beta 1/3 exhibits the opposite time course, being most intense 3-6 h after heat shock and returning to control levels by 48 h. The increase in TGF-beta s after hyperthermia could play a role in mediating the reported cardioprotective effects of heat shock.

Cells, Cultured↗

PubMed1993

Immunohistochemical localization of transforming growth factor-beta 1 in rats with experimental silicosis, alveolar type II hyperplasia, and lung cancer.

Immunohistochemical localization of transforming growth factor-beta 1 (TGF-beta 1) was studied in the lungs of rats given crystalline silica or ferric oxide by single intratracheal instillation. Ferric oxide elicited no progressive granulomatous reaction, no epithelial hyperplasia, and no lung tumors; no demonstrable reactivity to TGF-beta 1 was observed. Silica induced a granulomatous reaction with progressive fibrosis, adjacent alveolar type II hyperplasia, and alveolar carcinomas. Rabbit polyclonal antibodies to synthetic peptides corresponding to the first 30 amino acids of mature TGF-beta 1, anti-LC (1-30), and anti-CC (1-30) were used for the localization of intracellular and extracellular TGF-beta 1. An antibody to a peptide corresponding to amino acids 266-278 of the TGF-beta 1 precursor sequence, anti-Pre (266-278), was used to detect the TGF-beta precursor and the latency-associated peptide. Intracellular mature TGF-beta (anti-LC) was demonstrated in fibroblasts and macrophages located at the periphery of silicotic granulomas and in fibroblasts adjacent to hyperplastic type II cells. Extracellular mature TGF-beta 1 was localized in the connective tissue matrix of the granulomas and in the stroma of both hyperplastic type II cells and well-differentiated adenocarcinomas. Immunoreactivity to anti-Pre was localized, intracellularly, in hyperplastic alveolar type II cells and their proliferative lesions adjacent to granulomas, in adenomas, but not in adenocarcinomas. The hyperplastic type II cells appear to be the sites of production and secretion of TGF-beta 1, which may regulate their own growth and differentiation and mediate the production of extracellular TGF-beta 1-associated matrix. The lack of reactivity to TGF-beta 1 precursor in the adenocarcinomas is consistent with the loss of normal cellular differentiation and function. TGF-beta 1 appears to have a pathogenetic role in silica-induced mesenchymal and epithelial lesions. The role of TGF-beta 1 and other cytokines in silica-induced carcinogenesis requires further investigation.

Adenocarcinoma↗

PubMed1992

Induction of transforming growth factor beta 1 in human breast cancer in vivo following tamoxifen treatment.

We have investigated the ability of tamoxifen to regulate members of the transforming growth factor beta (TGF-beta) family in human breast cancers in vivo. Using immunohistochemical techniques, we find that 3 months of tamoxifen treatment causes a consistent induction of extracellular TGF-beta 1 in breast cancer biopsies, compared with matched pretreatment samples from the same patient. The induced TGF-beta is localized between and around stromal fibroblasts and appears to be derived from these cells. Lower levels of TGF-beta 1,-beta 2, and -beta 3 seen in epithelial cells were not altered by tamoxifen treatment. The increased stromal staining of TGF-beta 1 occurred in estrogen receptor-negative as well as estrogen receptor-positive tumors. These results provide in vivo evidence for a novel, estrogen receptor-independent mechanism of action for tamoxifen, involving the stromal induction of a potent growth inhibitor for epithelial cells.

Biomarkers, Tumor↗

PubMed1992

Release of a transforming growth factor (TGF)-beta 2-related suppressor factor from postimplantation murine decidual tissue can be correlated with the detection of a subpopulation of cells containing RNA for TGF-beta 2.

Postimplantation murine decidual tissue from allopregnant C3H mice has been shown to release in vitro a potent immunosuppressive factor closely related to transforming growth factor (TGF)-beta 2 but slightly lower in apparent molecular weight. Decidual suppressor factor (DSF) activity was first detected in decidual tissue supernatant at day 9.5 of gestation and reached a plateau by day 10.5 to 12.5. By Northern analysis of decidual and placental tissue with a simian TGF-beta 2 probe, two characteristic TGF-beta 2 mRNA transcripts were detected in decidual tissue. In situ hybridization analysis of C3H implant sites, with the simian (pGEM-G1G2) TGF-beta 2 riboprobe, revealed a small population of TGF-beta 2+ cells localized to postimplantation decidua basalis and metrial gland cell area after day 8.5. On and before day 8.5, when DSF was not detectable, few TGF-beta 2 mRNA+ cells were detected. To test for TGF-beta release in situ, sections of uterine tissue were stained with antibody specific for TGF-beta 2, that identified DSF in Western blots. In postimplantation tissues (day 9.5, 12.5) patchy anti-TGF-beta 2 staining was seen over decidual tissue. Before day 9.5, slight and diffuse staining over decidual tissue was present with more marked staining of extradecidual tissue. Very little staining was noted over day 9.5 decidual tissue by using anti-TGF-beta 1 antibody as a control; however, some staining was seen over postimplantation fetal trophoblast and myometrial tissue. Fractionation of disaggregated postimplantation decidua by velocity sedimentation revealed that TGF-beta 2 mRNA+ cells were predominantly small and sedimented in the same fraction(s) as those cells previously shown to release DSF in vitro. Thus, the release of TGF-beta 2 related DSF correlates with the in situ detection of TGF-beta 2 mRNA and the in situ release of TGF-beta 2 peptide. These studies suggest that DSF may be a form of TGF-beta 2 released by a population of small lymphocytic decidual suppressor cells.

Animals↗

PubMed1992

Transforming growth factor beta 1 as a biomarker for prostate cancer.

Using the mouse prostate reconstitution (MPR) model system, under conditions where the ras and myc oncogenes are introduced via a recombinant retrovirus into both the mesenchymal and epithelial compartments of the urogenital sinus, poorly differentiated prostate cancer is produced with high frequency (> 90%) using inbred C57BL/6 mice. Northern blotting and immunohistochemical analysis showed that the transition from benign prostatic hyperplasia (BPH) to prostate cancer is invariably associated with the induction of elevated transforming growth factor-beta 1 (TGF-beta 1) expression. Similar analysis of TGF-beta 1 in human BPH and prostate cancer is consistent with our MPR results and indicates that the accumulation of extracellular TGF-beta 1 is significantly more intense in prostate cancer compared to normal or benign prostate tissues. Interestingly, where benign pathologies are observed in the prostatic stroma in the presence of benign prostatic epithelium, extracellular TGF-beta 1 is seen predominantly in the stromal compartment. Experimental studies clearly demonstrate that mRNA levels of TGF-beta 1 and other growth related genes are regulated by androgens in prostate cancer cells. Overall, our results suggest that elevated TGF-beta 1 is involved in the development of prostate cancer. Direct determination of TGF-beta 1 levels and distribution as well as analysis of localized and systemic effects produced by TGF-beta 1 may serve as useful biomarkers for prostate cancer.

Animals↗

PubMed1992

Transforming growth factor beta 1 is an epithelial-derived signal peptide that influences otic capsule formation.

Interactions between epithelial and mesenchymal tissues in the developing inner ear direct the formation of its cartilaginous capsule. Recent work indicates that many growth factors are distributed in the early embryo in vivo in a temporal-spatial pattern that correlates with sites of ongoing morphogenetic events. We report here that the localization of transforming growth factor beta 1 (TGF-beta 1) in both epithelial and mesenchymal tissues of the mouse inner ear between 10 and 16 days of embryonic development (E10-E16). In addition, utilizing a high-density culture system as an in vitro model of otic capsule chondrogenesis, we show that modulation of chondrogenesis by TGF-beta 1 in cultured mouse periotic mesenchyme mimics the in vitro effects of otic epithelium on the expression of chondrogenic potential. We provide evidence of a causal relationship of this growth factor to otic capsule formation in situ by demonstrating that the actual sequence of chondrogenic events that occur in the developing embryo is reproduced in culture by the addition of exogenous TGF-beta 1 peptide. Furthermore, in cultures of mesenchyme containing otic epithelium, we demonstrate the localization of endogenous TGF-beta 1, first within the epithelial tissue and later within both the epithelium and its surrounding periotic mesenchyme, contrasted to an absence of endogenous TGF-beta 1 in cultures of mesenchyme alone. Our results suggest that TGF-beta 1 is one of the signal molecules that mediate the effects of otic epithelium in influencing the formation of the cartilaginous otic capsule.

Animals↗

PubMed1992

Regulation of mammary morphogenesis: evidence for extracellular matrix-mediated inhibition of ductal budding by transforming growth factor-beta 1.

Branching morphogenesis in the mammary gland involves focal regions of cell proliferation, the terminal and lateral ductal buds, that exist simultaneously with extensive regions of differentiated ducts in which budding and growth are actively suppressed. Exogenous transforming growth factor-beta 1 (TGF-beta 1) has previously been shown to locally inhibit the formation and growth of mammary ductal buds. Here we report that endogenous TGF-beta 1, produced by epithelial and stromal mammary cells, forms complexes with extracellular matrix (ECM) molecules surrounding those ductal structures in which budding is inhibited. The largest amounts of immunostainable TGF-beta 1 are found in mature periductal ECM, and the least in newly synthesized ECM. In all areas of active ductal growth, where DNA-synthetic buds were forming new ductal branches, we found a highly focal loss of TGF-beta 1 from the periductal ECM at the bud-forming region of the duct. When growth of the new buds terminated, the structures again became associated with TGF-beta-rich ECM. These findings indicate that ECM must reach a certain state of maturity before it becomes associated with TGF-beta 1 and that TGF-beta 1 can be depleted selectively from the periductal ECM at focal growth points. A different type of growth point, the alveolar (secretory) buds, was also investigated. These buds are known not to be inhibited by exogenous TGF-beta 1, and we found them not to be associated with changes in ECM-bound TGF-beta 1. Our results support the concept that the periductal ECM acts as a reservoir for TGF-beta 1 that functions to maintain an open pattern of mammary branching by inhibiting ductal, but not alveolar, bud formation.

Animals↗

PubMed1992

Localization and binding of transforming growth factor-beta isoforms in mouse preimplantation embryos and in delayed and activated blastocysts.

The stage and cell-specific accumulation of mammalian isoforms of transforming growth factor-beta (TGF-beta 1, TGF-beta 2, and TGF-beta 3) and TGF-beta binding were examined in the preimplantation embryo and in progesterone (P4)-treated delayed or P4 plus estradiol-17 beta (E2)-treated activated blastocysts in the mouse. Immunocytochemical studies revealed that while all three immunoreactive TGF-beta isoforms were present in one-cell embryos, very little or no immunostaining was observed in two-cell embryos. However, distinct immunostaining of these isoforms was again observed in four-cell embryos and persisted through the blastocyst stage. Among the isoforms studied, TGF-beta 2 immunostaining showed a unique pattern in late morulae. In many of these morulae, the staining was primarily observed in outside cells. However, in blastocysts, immunostaining for all three isoforms was present both in the inner cell mass (ICM) and trophectoderm (Tr). Immunostaining in sectioned blastocysts and immunosurgically isolated ICMs confirmed immunostaining in Tr and ICM cells. To ascertain whether preimplantation embryos can produce TGF-beta isoforms, immunostaining was performed in embryos grown in vitro from two-cell stage in simple balanced salt solution. Immunoreactive TGF-beta s 1-3 were present in embryos at all stages of development examined (four-cell embryos through blastocysts). The virtual absence of immunoactive TGF-beta s in two-cell embryos but their accumulation in embryos at later stages of development in vitro provides evidence that these growth factors were produced by embryos. In order to assess at what stages of development preimplantation embryos could be responsive to TGF-beta s, specific binding of [125I]TGF-beta 1 and [125I]TGF-beta 2 was performed in embryos and examined by autoradiography. Low levels of binding were first detected in eight-cell embryos. The binding increased in morulae followed by a further increase in blastocysts. Analysis of binding of [125I]TGF-beta 2 in immunosurgically isolated ICMs indicated that binding was primarily evident in Tr cells. Affinity labeling of TGF-beta 1 or TGF-beta 2 in Day 4 blastocysts revealed three classes of binding proteins with approximate molecular sizes of 65 kDa (type I), 90 kDa (type II), and greater than 250 kDa (type III), in addition to a doublet of 130 and 140 kDa proteins. This observation is similar to those reported for other cell types. The data suggest that embryos are likely to be responsive to TGF-beta s after the third cleavage.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1992

Localization of transforming growth factor-beta isotypes in lesions of the human breast.

Transforming growth factor-beta s (TGF-beta) comprise a highly conserved family of multifunctional cell regulatory peptides that may play a role in a variety of pathologic processes. To date, five TGF-beta isotypes have been identified, three of these in mammalian systems. A number of cultured human breast carcinoma cell lines produce biologically inactive latent TGF-beta and are growth inhibited by activated TGF-beta; TGF-beta production is estrogen-influenced in some of these cell lines. To investigate the potential role of the TGF-beta isotypes in human breast disease, we localized TGF-beta s 1, 2, and 3 immunohistochemically in normal breast, fibrocystic change, epithelial hyperplasia, sclerosing adenosis, fibroadenoma, cystosarcoma phyllodes, and several carcinoma variants. Transforming growth factor-beta s 1, 2, and 3 were identified intracellularly in most active mammary epithelia, regardless of the lesion, including carcinoma; the associated stroma contained little or no intracellular TGF-beta. An antibody that recognizes an extracellular conformation of TGF-beta stained normal intralobular stroma and, more extensively, the stroma of active fibroadenomas and low-grade phyllodes tumors and the desmoplastic stroma of carcinomas. The results indicate the potential for paracrine and autocrine regulation of the mammary gland by TGF-beta and suggest an association between TGF-beta and abnormal stromal proliferations. Altered expression of TGF-beta s 1, 2, and 3 at the protein level in mammary epithelia appears not to be a major feature of most breast lesions, raising the possibility that altered cellular response to the TGF-beta already present may play a role in the development of breast disease.

Breast↗

PubMed1992

Eosinophils in chronically inflamed human upper airway tissues express transforming growth factor beta 1 gene (TGF beta 1).

Transforming growth factor beta (TGF beta) is a multifunctional protein which has been suggested to play a central role in the pathogenesis of chronic inflammation and fibrosis. Nasal polyposis is a condition affecting the upper airways characterized by the presence of chronic inflammation and varying degrees of fibrosis. To examine the potential role of TGF beta in the pathogenesis of this condition, we investigated gene expression and cytokine production in nasal polyp tissues as well as in the normal nasal mucosa. By Northern blot analysis using a porcine TGF beta 1 cDNA probe, we detected TGF beta 1-specific mRNA in nasal polyp tissues, as well as in the tissue from a patient with allergic rhinitis, but not in the normal nasal mucosa. By the combination of tissue section staining with chromotrope 2R with in situ hybridization using the same TGF beta 1 probe, we found that approximately 50% of the eosinophils infiltrating the polyp tissue express the TGF beta 1 gene. In addition, immunohistochemical localization of TGF beta 1 was detected associated with extracellular matrix as well as in cells in the stroma. These results suggest that in nasal polyposis where eosinophils are the most prevalent inflammatory cell, TGF beta 1 synthesized by these cells may contribute to the structural abnormalities such as stromal fibrosis and basement membrane thickening which characterize this disease.

Chronic Disease↗

PubMed1992

Presence of transforming growth factor-beta and their selective cellular localization in human ovarian tissue of various reproductive stages.

Immunohistochemical studies were performed using specific polyclonal antibodies to transforming growth factor (TGF)-beta 1 and TGF-beta 2 to determine their presence and cellular localization in human ovarian tissues of various reproductive states. In the small ovarian follicles, the immunostaining for TGF-beta 1 was present in oocytes, follicle cells, and granulosa and theca cell layers. The level of immunostaining associated with granulosa and theca cell layers intensified as the size of the follicles increased. In the luteal tissue, both the small and large luteal cells immunostained for TGF-beta 1 and their intensities were similar to theca and granulosa cell layers, respectively. The patterns of immunostaining were similar in early (days 14-19), mid (days 22-25), and late (days 26-29) luteal phases; however, the intensity was highest at mid and decreased at late luteal phase. Corpus albicans showed a very weak immunostaining for TGF-beta 1, whereas ectopic pregnancy small luteal cells immunostained relatively intensely. The ovarian stromal, luteal tissue fibroblasts, and arterioles endothelial and smooth muscle cells were also immunostained for TGF-beta 1. The immunostaining of the ovarian tissues for TGF-beta 2 indicated that the theca cell layers were the exclusive cells in the follicles with intense immunostaining, which increased in the larger follicles. A low immunostaining was also observed in granulosa cell of the large follicles. In the luteal tissues, only small luteal cells showed intense immunostaining for TGF-beta 2, which was similar in intensity to that in the theca cells; however, the large luteal cells showed a low level of immunostaining at midluteal phase. The small luteal cells in corpus albicans and ectopic pregnancy luteal tissues retained their immunostaining for TGF-beta 2, but with lower intensity. Endothelial and smooth muscle cells of arterioles also immunostained for TGF-beta 2, but not ovarian stromal cells. Atretic follicles showed very low or no detectable immunostaining for TGF-beta 1 or TGF-beta 2. The results of present studies show that human ovarian tissue at all the reproductive states locally produces TGF-beta 1 and TGF-beta 2, and although TGF-beta 1 is present in most major ovarian cell types, TGF-beta 2 is only produced by theca cells in the follicles and small luteal cells in luteal tissues.

Endothelium, Vascular↗

PubMed1992

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.

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 (approximately 6.0, 5.0, 4.0, and 3.5 kilobases) in total uterine poly(A)+ RNA on D1-D6 and in poly(A)+ RNA from the deciduum and myometrium collected on D7 and D8 of pregnancy. These TGF beta 2 transcripts were also detected in isolated samples of deciduomata or myometrium obtained from D8 pseudopregnant mice in which the decidual cell reaction was induced experimentally on D4. The levels of these transcripts remained relatively constant during the periimplantation period. Northern blot analysis detected a 3.8-kilobase TGF beta 3 transcript in total uterine poly(A)+ RNA on D1-D6. This transcript was detected in myometrial RNA samples on D7 and D8 of pregnancy or D8 of pseudopregnancy, but was not detected in RNA from the deciduum on D7 and D8 or in that from deciduomata on D8. The effects of ovarian steroids on TGF beta 2 and TGF beta 3 mRNAs were examined in uteri of adult ovariectomized mice. Uterine TGF beta 2 or TGF beta 3 mRNA persisted in ovariectomized mice. However, an injection of E2 induced a rapid (6 h), but transient, induction (approximately 3- to 4-fold) of TGF beta 2 mRNA. An injection of P4 had no effect on TGF beta 2 mRNA levels, and coinjection of P4 with E2 did not antagonize the E2-stimulated transient accumulation of TGF beta 2 mRNA. In comparison, neither an injection of E2 nor one of P4 exerted significant effects on TGF beta 3 mRNA levels.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1992

Interactions between retinoids and TGF beta s in mouse morphogenesis.

Using immunocytochemical methods we describe the distribution of different TGF beta isoforms and the effects of excess retinoic acid on their expression during early mouse embryogenesis (8 1/2 - 10 1/2 days of development). In normal embryos at 9 days, intracellular TGF beta 1 is expressed most intensely in neuroepithelium and cardiac myocardium whereas extracellular TGF beta 1 is expressed in mesenchymal cells and in the endocardium of the heart. At later stages, intracellular TGF beta 1 becomes very restricted to the myocardium and to a limited number of head mesenchymal cells; extracellular TGF beta 1 continues to be expressed widely in cells of mesenchymal origin, particularly in head and trunk mesenchyme, and also in endocardium. TGF beta 2 is widely expressed at all stages investigated while TGF beta 3 is not expressed strongly in any tissue at the stages examined. Exposure of early neural plate stage embryos to retinoic acid caused reduced expression of TGF beta 1 and TGF beta 2 proteins but had no effect on TGF beta 3. Intracellular TGF beta 1 expression was reduced in all tissues except in the myocardium, while extracellular TGF beta 1 was specifically reduced in neuroepithelium and cranial neural crest cells at early stages. TGF beta 2 was reduced in all embryonic tissues. The down-regulation of intracellular TGF beta 1 was observed up to 48 hours after initial exposure to retinoic acid while some down-regulation of TGF beta 2 was still seen up to 60 hours after initial exposure.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Distribution of transforming growth factor beta in a two-week-old human embryo.

Using immunohistochemical methods we have investigated the presence of transforming growth factors beta 1, beta 2 and beta 1 precursor in a two-week-old bilaminar human embryo. TGF-beta 1 precursor was seen in both the epiblast and the hypoblast. In contrast to the widespread localization of TGF-beta 1 precursor in the embryo proper, antibodies to the mature TGF-beta 1 peptide localized preferentially to the hypoblast with only weak staining in the epiblast. Staining with antibodies to TGF-beta 2 was generally weak in both the epiblast and hypoblast layers of the embryo proper. These results show that TGF-beta 1 and beta 2 peptides are detectable as early as the second week of human development.

Embryo, Mammalian↗

PubMed1992

Discordant transforming growth factor beta 1 RNA and protein localization during chemical carcinogenesis of the skin.

Transforming growth factor beta (TGF-beta) inhibits proliferation of normal keratinocytes, and this response is retained, to variable extents, in benign tumors of the skin (S. Haddow, D. J. Fowlis, K. Parkinson, R. J. Akhurst, and A. Balmain, Oncogene, 6: 1465-1470, 1991). To investigate the profile of TGF-beta biosynthesis during various stages of chemical carcinogenesis of the skin, we used a combination of ribonuclease protection assay, in situ hybridization with gene-specific probes for TGF-beta 1, -beta 2, and -beta 3, and immunohistochemistry with isoform-specific antibodies against TGF-beta 1. Following 12-O-tetradecanoylphorbol-13-acetate treatment of adult mouse skin, there was a rapid induction of TGF-beta 1 protein. Intracellular TGF-beta 1 protein was localized to suprabasal keratinocytes, and the extracellular form was localized predominantly to the dermis. Despite ubiquitous induction of TGF-beta 1 protein by 12-O-tetradecanoylphorbol-13-acetate in various mouse strains, we noted strain-specific differences in the quantitative induction of TGF-beta 1 RNA. Papillomas and carcinomas induced in vivo had elevated levels of TGF-beta 1 RNA within the basal keratinocyte compartment but did not contain significant levels of TGF-beta 1 protein within the tumor. We postulate that the tumor evades TGF-beta 1-controlled negative growth regulation by altered translational and/or posttranslational processing mechanisms of this growth factor. Levels of TGF-beta 2 and -beta 3 RNA were not elevated at any stage of chemical carcinogenesis of the skin.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1991

Successful treatment of experimental allergic encephalomyelitis with transforming growth factor-beta 1.

Transforming growth factor-beta 1 (TGF-beta 1) is a multifunctional cytokine with immunosuppressive effects on T cells in vitro. Experimental allergic encephalomyelitis is an archetypal T cell-mediated autoimmune demyelinating disease of the central nervous system that often serves as a model for multiple sclerosis. In vivo administration of TGF-beta 1 into SJL mice was successful in reducing the incidence of clinical disease and the histologic severity of inflammation and demyelination in the brain and spinal cord. Immunohistochemical studies performed on control animals showed that TGF-beta-1, -2, and -3 were present in inflammatory perivascular lesions in the brain. The use of a naturally occurring cytokine with immunoregulatory functions in the treatment of an autoimmune disease is novel. However, potential long term complications of such therapy must be addressed before its use in human autoimmune disease such as multiple sclerosis.

Animals↗