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PubMed1997

Complex regulation of transferrin receptors during erythropoietin-induced differentiation of J2E erythroid cells--elevated transcription and mRNA stabilisation produce only a modest rise in protein content.

The regulation of transferrin-receptor synthesis was studied in J2E erythroid cells induced to differentiate with erythropoietin. Nuclear run-on assays demonstrated that transcription of the transferrin-receptor gene rose markedly after erythropoietin treatment. In addition, transferrin-receptor mRNA was stabilised and this was associated with an increase in the activity of the RNA-binding protein IRP (iron regulatory protein). As a result of increased transcription and mRNA stabilisation, steady-state RNA levels increased 10-20-fold. However, despite these large increases in mRNA, translation only doubled; consequently, modest increases in total protein and surface transferrin receptors were observed. Moreover, this rise in transferrin receptors was transient, and correlated with a burst of proliferation shortly after erythropoietin treatment. The expected inverse relationship between transferrin receptors and ferritin did not occur during J2E maturation as translation of both ferritin subunits increased when transferrin-receptor mRNA levels rose. Analysis of mutant J2E clones incapable of synthesising haemoglobin revealed that surface transferrin-receptor levels were only 15-25% that of the parental erythroid line. We propose that the surface expression of transferrin receptors in J2E cells is governed by three factors: basal levels essential for normal growth in culture; elevated levels needed for haemoglobin synthesis; and a transient erythropoietin-induced increase that is required for the final burst of proliferation. It was concluded that the regulation of transferrin-receptor production in erythropoietin-stimulated J2E cells is complex and that there are several sites of control.

Animals↗
PubMed2001

Regulation of the inhibitor-of-apoptosis family member survivin in normal cord blood and bone marrow CD34(+) cells by hematopoietic growth factors: implication of survivin expression in normal hematopoiesis.

The inhibitor-of-apoptosis protein survivin is expressed in most cancers and leukemias and during fetal development, but not in most normal adult tissues. Survivin expression was analyzed in umbilical cord blood (UCB) and adult bone marrow CD34(+) cells and in the factor-dependent MO7e cell line; also investigated was whether survivin expression was regulated by hematopoietic growth factors. Survivin messsenger RNA (mRNA) and protein were expressed in fresh UCB and marrow CD34(+) cells. The combination of thrombopoietin, Flt3 ligand, and stem cell factor upregulated survivin expression in CD34(+) cells within 24 hours; survivin expression was cell-cycle related and highest during G2/M, whereas growth-factor withdrawal resulted in decreased survivin expression. Cell-cycle fractionation of UCB CD34(+) with Hoechst-33342/pyronin-Y demonstrated that survivin message was undetectable in freshly isolated G0 cells, but present in G1 cells. After cytokine stimulation, survivin mRNA and protein expression were observed in both G0 and G1 CD34(+) cells as well as in cells that had progressed to S and G2/M phase, indicating that survivin expression is regulated in all phases of the cell cycle. This contrasts with the expression of survivin predominantly during G2/M in cancer cells. In CD34(+) cells and MO7e cells, growth factor-mediated upregulation of survivin was associated with inhibition of apoptosis, and downregulation of survivin was coincident with increased apoptosis. Furthermore, an inverse correlation between survivin and active caspase-3 was observed in CD34(+) cells. These findings demonstrate that survivin is not a cancer-specific antiapoptotic protein and plays a regulatory role in normal adult hematopoiesis.

Antigens, CD34↗
PubMed1983

Physiology and ecology of the vagina.

The human vagina is lined by stratified squamous epithelium which has no glands. Major components of the vaginal secretions are transudate through the vaginal walls, desquamating epithelial cells, cervical mucus, fluids from the upper genital tract, and leukocytes. Estrogens and sexual stimulation are examples of factors which increase vaginal fluid. Major organic constituents of the vaginal fluid are proteins, carbohydrates, and fatty acids. Organic acids arise as metabolic byproducts of vaginal bacterial flora, cause the vaginal odor, and show cyclic changes except in oral contraceptive users. Qualitative and quantitative studies in humans as well as animal model studies have confirmed that the vaginal flora is a dynamic and closely interrelated system. Lactobacilli are most prevalent, but many other facultative and anaerobic organisms are present. An inverse relationship exists between the concentration of lactobacilli and other bacteria such as anaerobes. Aerobic bacteria decrease premenstrually whereas anaerobes, in general, remain at constant levels. During menarche, pregnancy, postpartum period, menopause, and postoperative trauma, dramatic changes occur in the microbial flora. The role of an IUD in causing changes in the microbial flora is under great scrutiny at the present time. Overall, disturbances in the vaginal ecosystem may have a potential impact on many diseases, and thus deserve careful studies.

Adolescent↗
PubMed1991

The v-src oncogene blocks the differentiation of a murine myeloid progenitor cell line and induces a tumorigenic phenotype.

We have investigated the ability of the v-src oncogene to block the differentiation of the murine myeloid progenitor cell line 32D cl3. In response to granulocyte-colony stimulating factor (G-CSF), 32D cl3 cells are induced to differentiate into mature granulocytes (Valtieri et al., 1987). In contrast, no differentiation was observed following G-CSF treatment of 32D cl3 cells infected with a murine retrovirus carrying the wild-type v-src oncogene. Furthermore, cells infected with a v-src temperature-sensitive (ts) mutant did not differentiate at the permissive temperature, however, at the nonpermissive temperature G-CSF induced granulocytic differentiation. Differentiation of 32D cl3 cells infected with ts WP31A (ts LA31A src gene inserted into amphotropic murine leukemia virus 4070A; Anderson et al., 1987) occurred with the same kinetics as uninfected 32D cl3 cells. Temperature-shift experiments indicate that after 72 hours of treatment with G-CSF at the nonpermissive temperature, approximately half of the 32D cl3 cells infected with ts WP31A virus become committed to differentiation. Prior to that time, activation of v-src by shifting the cells to the permissive temperature resulted in the presence of only undifferentiated blast cells after six days in culture. In contrast to normal 32D cl3 cells, cells infected with the wild-type v-src were tumorigenic when injected into nu/nu Swiss mice. Lesions appeared in the spleen, liver, kidney, lungs and lymph nodes following subcutaneous injection. Growth factor-independent cells were recovered from the tumor, spleen, bone marrow and a lymph node of tumor-bearing nude mouse. Analysis of the proviral integration site by inverse polymerase chain reaction (PCR) demonstrated that the tumor cells were of donor cell origin.

Animals↗
PubMed2002

Constitutive activity of G-protein coupled receptors: emphasis on serotonin receptors.

Several lines of evidence indicate that G-protein coupled receptors (GPCR) may exist in a state that allows a tonic level of stimulation in vivo (constitutive activity). Several native forms of GPCR, when expressed in recombinant cell lines, display significant signal transduction stimulation in the absence of activating ligand. Many GPCR, including three serotonin receptors, display robust constitutive activation upon the mutation of a single amino acid, indicating mutations producing inappropriate constitutive activation may be etiological factors in diseases. If constitutive activity of GPCR is as common a phenomenon as some researchers suspect, this would suggest significant alterations in the classical model of ligand-receptor interactions. One of the most significant implications of constitutive activity for pharmacologists and medicinal chemists, is the possibility of developing drugs that lower the level of constitutive activity. Such compounds have been termed inverse agonists . These drugs, in theory, would have different physiological effects, and therefore possibly different therapeutic potential, than classical competitive receptor antagonists ( neutral antagonists ). Theoretical issues concerning constitutive activity in the GPCR family and some of the evidence supporting the existence of constitutive activity in the GPCR family is reviewed. Studies are presented demonstrating the procedures for producing and characterizing constitutive activated forms of serotonin receptors, including the demonstration of inverse agonist activity of drugs on these receptors.

Animals↗
PubMed2000

Maturation of dendritic cells leads to up-regulation of cellular FLICE-inhibitory protein and concomitant down-regulation of death ligand-mediated apoptosis.

Dendritic cells (DCs) disappear from lymph nodes 1 to 2 days after antigen presentation, presumably by apoptosis. To evaluate the role of death ligands in elimination of DCs, we analyzed the sensitivity of human DCs to CD95 ligand (CD95L) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). We found mature DCs to be resistant to killing via CD95L or TRAIL, whereas only immature DCs were partially sensitive. However, all DC populations expressed CD95, TRAIL-R2, and TRAIL-R3 at comparable levels, suggesting that sensitivity to death ligand-induced DC apoptosis is not regulated at the receptor level. Interestingly, mature DCs highly expressed the caspase 8 inhibitory protein cFLIP, whereas only low levels were detected in immature DCs. Thus, death ligand sensitivity proved to be dependent on DC maturation and inversely correlated with expression levels of cFLIP. Induction of apoptosis by TRAIL or CD95L does not seem to play a role in the elimination of mature DCs, but instead might serve to regulate immature DC populations.

Antigens, CD↗
PubMed2003

HGF receptor up-regulation contributes to the angiogenic phenotype of human endothelial cells and promotes angiogenesis in vitro.

Hepatocyte growth factor (HGF) is a mesenchyme-derived pleiotropic growth factor and a powerful stimulator of angiogenesis, which acts on cells by binding to the c-met receptor. The exact role of the endogenous HGF/c-met system in one or more steps of the angiogenic process is not completely understood. To contribute to this question we used immunocytochemical analysis, Western blotting, and reverse transcription-polymerase chain reaction to study the expression of c-met in endothelial cells cultured in different growth conditions. We found that c-met is not colocalized with vascular endothelial (VE)-cadherin in cell-cell junctions. c-met and VE-cadherin were shown to be inversely regulated by cell density, at both the protein and the mRNA levels. We established that c-met is up-regulated during the in vitro recapitulation of several steps of angiogenesis. The c-met expression was increased shortly after switching to angiogenic growth conditions and remained high during the very first steps of angiogenesis, including cell migration, and cell proliferation. The endothelial cells in which the expression of c-met was up-regulated were more responsive to HGF and exhibited a higher rate of morphogenesis. Moreover, the antibody directed against the extracellular domain of the c-met inhibited angiogenesis in vitro. Our results suggest that c-met is a marker of angiogenic phenotype for endothelial cells and represents an attractive target for the development of new antiangiogenic therapies.

Antibodies↗
PubMed2005

Cloning and characterization of the novel chimeric gene TEL/PTPRR in acute myelogenous leukemia with inv(12)(p13q13).

We have cloned a novel TEL/protein tyrosine phosphatase receptor-type R (PTPRR) chimeric gene generated by inv(12)(p13q13). PTPRR is the first protein tyrosine phosphatase identified as a fusion partner of TEL. The chimeric gene fused exon 4 of the TEL gene with exon 7 of the PTPRR gene, and produced 10 isoforms through alternative splicing. Two isoforms that were expressed at the highest level in the leukemic cells could have been translated into COOH-terminally truncated TEL protein possessing the helix-loop-helix domain (tTEL) and TEL/PTPRR chimeric protein linking the helix-loop-helix domain of TEL to the catalytic domain of PTPRR. These two mutant proteins exerted a dominant-negative effect over transcriptional repression mediated by wild-type TEL, although they themselves did not show any transcriptional activity. Heterodimerization with wild-type TEL might be an underlying mechanism in this effect. TEL/PTPRR did not exhibit any tyrosine phosphatase activity. Importantly, overexpression of TEL/PTPRR in granulocyte macrophage colony-stimulating factor-dependent UT7/GM cells resulted in their factor-independent proliferation, whereas overexpression of tTEL did not. After cytokine depletion, phosphorylated signal transducers and activators of transcription 3 (STAT3) significantly declined in mock cells, but remained in both tTEL- and TEL/PTPRR-overexpressing cells. Loss of tumor suppressive function of wild-type TEL and maintenance of STAT3-mediated signal could at least partly contribute to the leukemogenesis caused by inv(12)(p13q13).

Adult↗
PubMed1995

The significance of urokinase- type plasminogen activator, its inhibitors, and its receptor in ascites of patients with epithelial ovarian cancer.

BACKGROUND: Strong correlations have been reported between expression of urokinase-type plasminogen activator (uPA) and poor prognosis in several human carcinomas. The clinical significance of secreted levels of uPA, its receptor (uPAR), and its inhibitors (PAI-1 and PAI-2) in the ascites of patients with epithelial ovarian cancer patients was investigated. METHODS: uPA, uPAR, PAI-1, and PAI-2 were measured in the primary ascites of 36 patients with epithelial ovarian cancer by enzyme-linked immunosorbent assay, and normalized to protein content. The relationship between levels of these factors in ascites and clinicopathologic variables, survival, and disease free interval (DFI) was studied. Because high levels of macrophage colony stimulating factor (CSF-1) in ascites is a known poor prognostic indicator for ovarian cancer, the effect of CSF-1 on secretion of PAI-2 by ovarian cancer cells was also examined in vitro. RESULTS: High uPA levels per se did not correlate with either survival or DFI. However, the ratio of uPAR normalized for uPA content correlated inversely with FIGO stage and residual disease, with a significant association between high uPAR/uPA level and prolonged survival and DFI. High PAI-1 levels (> 0.120 ng/mg) proved to be a good prognostic factor, correlating with both prolonged DFI and residual disease < or = 5 cm among Stage 3 patients. Conversely, high levels of PAI-2 (> 0.061 ng/mg) indicated a poor prognosis in Stage 3 patients, as high PAI-2 levels were associated with shorter DFI and survival. CSF-1 stimulated the secretion of PAI-2 by 2.4-fold in Bix3 ovarian carcinoma cells. Multivariate analysis revealed that the two independent prognostic factors for DFI in Stage 3 patients were PAI-1 and PAI-2; Stage 3 patients with high secreted PAI-1 and low PAI-2 levels have a median DFI that was prolonged by 30 months relative to the rest of the group. CONCLUSION: Secreted uPAR/uPA appears to measure tumor burden and predicts prolonged DFI and survival, but was not found to be an independent prognostic factor on multivariate analysis. High levels of PAI-1 in ascites were independently associated with prolonged DFI among Stage 3 patients. Therefore, secreted uPAR and PAI-1 may modulate uPA activity and lead to improved outcome. This contrasts with the finding that secreted PAI-2 is an independent factor indicating poor prognosis, which may relate in part to the actions of CSF-1. This study emphasizes the importance of uPA, its receptor, and its inhibitors in patients with epithelial ovarian cancer.

Adult↗
PubMed2003

Influence of maternal immunity on antibody and T-cell response in mice.

The prevalence of maternal antibodies (Abs) and an immature neonate immune system, which is inclined to a T-helper 2 (Th2) response, are factors that counteract active immunization in early life. In a mouse model, the maternal influence on an active immunization of 2-day-old offspring with Sendai virus (SV) envelope proteins was explored. Maternal immunizations were conducted with the same SV antigen preparation as used for offspring immunization, presented in three different formulations, namely micelles of SV (SV-MIC), Al(OH)(3)-adjuvanted SV-MIC (SV-aluMIC) for Th2 and immune stimulation complex (iscom)-adjuvanted SV (SV-ISC) for Th1. An inversely correlation was found between the immunoglobulin G2a (IgG2a) Abs of the mothers and the interleukin 5 (IL-5) levels of the offspring. Although a maternally derived immunity induced by SV-aluMIC suppressed both B- and T-cell responses of the newborn to SV-ISC immunization, significant priming effects of the neonatal immunization on IgG2a Abs and IFN-gamma levels were recorded after reimmunization at adult age.

Animals↗
PubMed2005

Nitric oxide regulates angiogenesis through a functional switch involving thrombospondin-1.

Nitric oxide (NO) donors have been shown to stimulate and inhibit the proliferation, migration, and differentiation of endothelial cells in vitro and angiogenesis in vivo. Recently, we have shown distinct thresholds for NO to regulate p53-Ser-15P, phosphorylated extracellular signal-regulated kinase (pERK), and hypoxia inducible factor 1alpha in tumor cells. Because these signaling pathways also promote the growth and survival of endothelial cells, we examined their roles in angiogenic responses of venous endothelial cells and vascular outgrowth of muscle explants elicited by NO. An additional protein involved in the regulation of angiogenesis is thrombospondin-1 (TSP1), a matricellular glycoprotein known to influence adhesion, migration, and proliferation of endothelial cells. Here we demonstrate a triphasic regulation of TSP1 mediated by a slow and prolonged release of NO that depends on ERK phosphorylation. Under conditions of 5% serum, a 24-h exposure of NO donor (0.1-1,000 microM) mediated a triphasic response in the expression of TSP1 protein: decreasing at 0.1 microM, rebounding at 100 microM, and decreasing again at 1,000 microM. Under the same conditions, we observed a dose-dependent increase in P53 phosphorylation and inverse biphasic responses of pERK and mitogen-activated protein kinase phosphatase-1. Both the growth-stimulating activity of low-dose NO for endothelial cells and suppression of TSP1 expression were ERK-dependent. Conversely, exogenous TSP1 suppressed NO-mediated pERK. These results suggest that dose-dependent positive- and negative-feedback loops exist between NO and TSP1. Limiting TSP1 expression by positive feedback through the ERK mitogen-activated protein kinase pathway may facilitate switching to a proangiogenic state at low doses of NO.

Animals↗
PubMed1993

M-CSF gene transduction in multidrug-resistant human cancer cells to enhance anti-P-glycoprotein antibody-dependent macrophage-mediated cytotoxicity.

A human macrophage-colony-stimulating-factor (M-CSF) gene inserted into an expression vector (pRc/CMV-MCSF) was transfected into multidrug-resistant (MDR) human ovarian cancer cells (AD10) to induce secretion of human M-CSF into the medium. The M-CSF level in the culture medium of the transfected cells reached 100 ng/ml after 7 days, and the ability of the cells to secrete M-CSF was stable for at least 3 months. Transfection of the M-CSF gene did not result in any change in expression of MDRI (P-glycoprotein), proliferation or chemosensitivity of the cells from those of the parent cells. There was also no difference between the transfected and the parent cells in susceptibility to NK cell- or interleukin-2-activated killer-cell-mediated cytotoxicity. Human blood monocytes that had been incubated for 4 days in medium with the culture supernatant of MH-AD10 cells exhibited higher ADCC activity than untreated monocytes against MDRI-positive cancer cells. This effect of the supernatant of AD10 cells was completely abolished by its treatment with a monoclonal anti-M-CSF antibody (MAb). When transfected human MDR cells were injected into nude mice, an inverse correlation was seen between the ability of the cells to produce M-CSF and their tumorigenicity. Thus, gene modification of MDR cancer cells seems hopeful as a therapeutic method for enhancing anti-MDRI-MAb-dependent macrophage-mediated cytotoxicity against human MDR cancer cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Metabolic features of polycystic ovary syndrome are found in adolescent girls with hyperandrogenism.

Recently, we reported that hyperandrogenism in adolescent girls is accompanied by augmented LH pulsatility and elevated LH/FSH ratio with increased ovarian volume. Together with higher concentrations of 17-hydroxyprogesterone, androstenedione, testosterone, and estrone that are ovarian in origin, these neuroendocrine features are identical to those seen in adult women with polycystic ovary syndrome. In the present study, we report the metabolic characteristics of these hyperandrogenic adolescent girls. The GH insulin-like growth factor I (IGF-I)-binding protein (BP)-3 axis, insulin sensitivity, and insulin-IGFBP-1/insulin sex hormone binding globulin axes were evaluated in 13 adolescent girls (ages 11-18 yr) with mild to moderate signs of hyperandrogenism (HA) and 28 age-matched normal girls. Insulin sensitivity was assessed by a frequent-sample iv glucose tolerance test (ivGTT, 0.3 g/kg). Twenty-four hour blood samples were obtained at 10-min intervals and were used to determine GH pulsatility (20-min samples), IGFBP-3 levels (0800-0900 h), and fluctuations of insulin, IGFBP-1, and IGF-I (hourly samples) during feeding and fasting phases of the day. In addition, GH responses to GHRH stimulation (1 microgram/kg) were assessed. Fasting insulin concentrations, but not plasma glucose levels, were significantly elevated in the HA group compared with those in the normal group (256 +/- 35 vs. 103 +/- 24 pmol/L, P = 0.0008), as were insulin responses to ivGTT and meals (P < 0.01) and 24-h mean insulin concentrations (P < 0.01). Thus, hyperinsulinemia with normal fasting glucose levels in HA girls may reflect insulin resistance, as suggested by the increased ratio of insulin and glucose (P < 0.001). All measures of insulin were correlated with body mass index (BMI); however, insulin remained significantly higher in the HA group after correcting for BMI, suggesting that decreased insulin sensitivity was related to other factors in addition to BMI. Twenty-four hour IGFBP-1 concentrations showed a diurnal pattern with an inverse relationship to insulin, and 24-h mean concentrations were lower in the HA group (0.35 +/- 0.13 vs. 0.76 +/- 0.09 micrograms/L, P = 0.02). Reduced sex hormone binding globulin levels were also inversely related to insulin levels (P = 0.0007). In contrast, GH pulsatile characteristics and IGF-I/IGFBP-3 levels, as well as GH responses to GHRH, were similar between the groups.(ABSTRACT TRUNCATED AT 400 WORDS)

17-alpha-Hydroxyprogesterone↗
PubMed1995

Expression of the Wilms' tumor gene WT1 in human malignant mesothelioma cell lines and relationship to platelet-derived growth factor A and insulin-like growth factor 2 expression.

Mutations in the WT1 tumor suppressor gene are known to contribute to the development of Wilms' tumor (WT) and associated gonadal abnormalities. WT1 is expressed principally in the fetal kidney, developing gonads, and spleen and also in the mesothelium, which lines the coelomic cavities. These tissues develop from mesenchymal components that have subsequently become epithelialized, and it has therefore been proposed that WT1 may play a role in this transition of cell types. To test the possible involvement of this gene in malignant mesothelioma, we have first studied its expression in a panel of human normal and malignant mesothelial cell lines. WT1 mRNA expression levels varied greatly between the cell lines and no specific chromosomal aberration on 11p, which could be related to the variation in WT1 expression in these cell lines, was observed. Furthermore, no gross deletions rearrangements, or functionally inactivating point mutations in the WT1 coding region were identified. All four WT1 splice variants were observed at similar levels in these cell lines. The WT1 gene encodes a zinc-finger transcription factor and the four protein isoforms are each believed to act as transcriptional repressors of certain growth factor genes. Lack of WTI expression in thus predicted to result in growth stimulation of tumor cells. Binding of one particular WT1 isoform construct to the insulin-like growth factor 2 (IGF2) and platelet-derived growth factor A (PDGFA) gene promoters has been demonstrated to result in repression of these genes in transient transfection studies. Analysis of IGF2 and PDGFA mRNA expression levels compared with WTI mRNA expression levels failed to demonstrate an inverse correlation in the mesothelial cell lines, which endogenously express these genes. Finally, the putative role of WT1 in the transition of cell types was investigated. No obvious correlation between WT1 expression levels and cell morphology of the malignant mesothelial cell lines was evident from this study. Moreover, no change in WT1 expression was observed in normal mesothelial cells which were, by alteration of culture conditions, manipulated to switch from the mesenchymal to epithelial morphology.

Base Sequence↗
PubMed1997

Identification of a novel transferable cis element in the promoter of an estrogen-responsive gene that modulates sensitivity to hormone and antihormone.

The estrogen receptor (ER) is a ligand-regulated transcription factor that acts at the promoters of estrogen-regulated genes to modulate their expression. In the present study, we examined three estrogen-regulated promoters, namely the rat progesterone receptor gene distal (PRD) and proximal (PRP) promoters and the human pS2 gene promoter, and observed marked differences in their sensitivity to stimulation by estrogen and repression of estrogen-stimulated transcription by antiestrogen (AE)-occupied ER. ER-containing MCF-7 human breast cancer cells were transfected with reporter gene constructs containing estrogen response elements upstream of the three gene promoters. In this system, PRP and PRD showed similar dose-response curves for stimulation by estradiol whereas pS2 was activated by even lower concentrations of estradiol. By contrast, PRD was much less sensitive to repression of estrogen-stimulated activity by all AEs studied, relative to the PRP and the pS2 promoters. Using deletion and mutational analysis, we have identified a transferable cis element at -131 to -94 bp in PRD that is involved in modulating the sensitivity of this promoter to both estrogens and AEs. The element reduced the magnitude of estrogen-stimulated activity, enhanced the ability of AEs to repress estrogen-stimulated activity, and elicited similiar effects when transferred to the promoter of another estrogen-responsive gene. Thus, removal of this region from PRD further accentuated the insensitivity of this promoter to AE while enhancing its sensitivity (both EC50 and fold induction) to estrogen. Gel mobility shift assays showed that proteins from nuclear extracts of MCF-7 cells interact with this element and that the binding of these proteins is inversely correlated with the transcriptional effectiveness of the ER. The findings demonstrate that a specific cis element from the promoter of an estrogen-responsive gene can alter the transcriptional activity of hormone and antihormone-occupied receptor bound at its response element near the promoter. Such ligand response modulatory elements, and changes in the levels and activity of factors that bind to such elements, may underlie the different sensitivities of steroid hormone-regulated genes to both hormones and antihormones.

Animals↗
PubMed2003

Monocyte-derived RANTES is intrinsically elevated in periodontal disease while MCP-1 levels are related to inflammation and are inversely correlated with IL-12 levels.

Bacteria colonizing tooth surfaces are essential in the induction of an inflammatory response in the periodontal tissues, but do not cause periodontitis in everyone, implicating differences in the host immune response. These possible differences were studied using lipopolysaccharide (LPS)-stimulated whole blood cell cultures (WBCC), which revealed a down regulation of monocyte derived interleukin-12 (IL-12p70) in untreated periodontitis patients and an up regulation after therapy. IL-12p70 is a crucial factor in the differentiation of Th1 cell responses. Since CC chemokines are able to influence the T cell differentiation via cytokine secretion in antigen-presenting cells, the production of CC chemokines in periodontitis was evaluated. Therefore WBCC were stimulated with LPS from Escherichia coli for 18 h and the levels of IL-12p70 and CC chemokines were measured in the supernatants by ELISA. Untreated periodontitis patients released 2 fold more RANTES (regulated on activation normal T cell expressed and secreted) (P = 0.01) and lower levels of IL-12p70 in comparison to controls (P < 0.05). A trend towards higher levels of macrophage chemoattractant protein-1 (MCP-1) (P = 0.07) was also seen in untreated periodontitis patients; while similar levels of monocyte derived chemokine (MDC) and macrophage inflammatory proteins-1 alpha and -1 beta (MIP-1 alpha and -1 beta) were found. After periodontal therapy no changes were seen with regard to MDC, MIP-1 alpha, MIP-1 beta and RANTES, whereas the MCP-1 levels decreased (P < 0.05) and the IL-12p70 levels strongly increased (P < 0.01). The data showed a consistent inverse correlation between the levels of MCP-1 and IL-12p70, and their proportional changes after therapy correlated with the clinical inflammatory response after therapy. This indicates that the disease state regulates the release of IL-12p70 and MCP-1 in E. coli LPS-stimulated WBCC. In contrast, the persistent augmented levels of RANTES after therapy are suggestive for an intrinsic behaviour.

Adult↗
PubMed1996

Serum levels of insulin-like growth factor-I, -II and insulin-like growth factor binding proteins -2 and -3 in children with acute lymphoblastic leukaemia.

UNLABELLED: The insulin-like growth factor (IGF) signaling pathway may be of importance for the proliferation of different tumours (e.g. breast cancer and Wilms tumour). The bioavailability of both IGF-I and IGF-II is regulated by specific IGF-binding proteins (IGFBPs). IGFBP-2 is the predominant binding protein during fetal life, where it is expressed in most tissues. In contrast, postnatally it is mainly released by specific cell types (hepatocytes, astroglia, kidney cells, prostate cells) and a range of tumour cell lines. Furthermore, phytohaemagglutinin stimulated normal lymphoblasts and malignant lymphoblasts express IGFBP-2. In order to investigate the IGF regulatory pathway in leukaemia serum levels of IGF-I, IGF-II, IGFBP-2 and IGFBP-3 were determined in 28 leukaemic children. Whereas serum levels of IGF-I (mean/range: -2.7/-0.1 to -6.7 SDS), IGF-II (-3.6 SDS/-1.3 to -8.7) and IGFBP-3 (-2.0/+2.2 to -7.1 SDS) were significantly decreased comparable to levels in growth hormone deficiency, IGFBP-2 levels (+4.0/-0.45 to +7.4 SDS) were found to be markedly elevated and inversely correlated to IGF-I (r = -0.51, P = 0.013). After haematological remission upon chemotherapy all four parameters had normalized in the 16 re-investigated children. Similar findings have been observed in one boy with a relapse including CNS leukaemia. CONCLUSION: This study demonstrates that the proliferation of malignant lymphoblasts (at diagnosis vs treatment) occurs in the presence of decreased serum levels of IGF-I, IGF-II and IGFBP-3 and that diminished production of these peptides may contribute to impaired growth. It further indicates that serum levels of IGFBP-2 may be directly related to the proliferation of lymphoblasts.

Adolescent↗
PubMed2002

The effect of endurance-type exercise training on growth mediators and inflammatory cytokines in pre-pubertal and early pubertal males.

Recent studies demonstrate an unexpected reduction in circulating levels of IGF-I after 5 wk of endurance-type exercise training in adolescent boys and girls and prepubertal girls. We hypothesized that the reduction in IGF-I would be accompanied by a training-associated stimulation of proinflammatory cytokines IL-1beta, IL-6, or tumor necrosis factor-alpha (TNF-alpha), each of which can inhibit the GH-->IGF-I axis. Healthy boys (age range 9-11 y old, mean Tanner 1.7) volunteered for the study and were randomized to control (n = 14) and training groups (n = 12) for 5 wk. After the intervention, significant increase in fitness was observed in the training group but not control group. Although IGF-I was correlated at baseline to peak oxygen consumption in all subjects, there was a significant decrease in IGF-I and IGF binding protein-3 in the training subjects (-12.8 +/- 7.3% and -17.5 +/- 7%, respectively, p < 0.05). In contrast, IGF binding protein-2, known to inhibit anabolic effects of IGF-I, increased in the training subjects (27.8 +/- 11%, p < 0.02) as did IL-1beta and TNF-alpha (51.5 +/- 30.22%, p < 0.02, and 44.5 +/- 23.2%, p < 0.02, respectively). Finally, we also found that GHBP was inversely correlated with fitness, suggesting altered GH function in more-sedentary boys. Thus, these data support the hypothesis that a sustained increase in physical activity can stimulate proinflammatory cytokines, which may contribute to suppression of the GH-->IGF-I axis. Physical activity can influence growth and development through its influence on anabolic and catabolic mediators.

Body Constitution↗