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PubMed1997

Modulation of the phenotypic and functional properties of phagocytic macrophages by wear particles from orthopaedic implants.

An attempt was made to assess the local chronic inflammatory response in patients with failed orthopaedic implant that is clinically associated with osteolysis, bone and bone marrow necrosis. The main objective was to analyse the heterogeneity of the macrophage functional subsets in the bone-implant interface membrane and to evaluate their possible role in the development of an erosive inflammatory lesion within the bone. Immunohistology was performed on 21 specimens of the bone-implant interface obtained from 17 patients during revision arthroplasty, and synovial membranes from rheumatoid (RA, n=4), and osteoarthritis (OA, n=4) patients. Three well-characterized monoclonal antibodies (MAb) recognizing antigenic determinants on specific functional subsets of macrophages (Mphi) were used. RFD1 (interdigitating reticulum cells/antigen presenting cells, (APC), RFD7 (mature phagocytic macrophages), and RFD9 epithelioid cells and foreign body giant cells (FBGC). RFD1 was expressed on a variable number of perivascular and synovial lining Mphi in both RA and OA synovia, at a frequency of 25%-40%. In cases with total joint replacements, the interface showed a marked increase in the expression of RFD1 (20%-90%). A considerably greater percentage of RFD1 positive Mphi and FBGC was noted in the interfaces from cases with a high level of detectable metal particulate wear debris (mean 80%, range 60%-90%) than in cases with polyethylene wear debris (mean 30%, range 0%-50%), p 0.0001. RFD7 labelled most tissue Mphi in each group. Immunoreactivity for RFD9 was restricted to FBGC in all cases analysed. The finding of elevated expression of RFD1 on metal-containing Mphi and FBGC in the bone-implant interface suggests an increase in antigen-presenting phenotype and indicates that metal particles have more impact in the induction of immune-mediated responses. Such responses are characterized by sustained cellular hyperreactivity and phenotypic changes in Mphi subsets.

Journal Article↗
PubMed2003

Expression of CXCR1 and CXCR2 receptors in malignant melanoma with different metastatic potential and their role in interleukin-8 (CXCL-8)-mediated modulation of metastatic phenotype.

In the present study, we examined the autocrine/paracrine role of IL-8 in melanoma growth and metastasis by analyzing the expression and functional significance of IL-8 receptors, CXCR1 and CXCR2 in human malignant melanoma cells with different metastatic potential. CXCR1 and CXCR2 mRNA and protein levels were analyzed by reverse trannscriptase-based polymerase chain reaction, immunohistochemistry, immunoprecipitation, flow cytometry and ligand binding assay in melanoma cells in vitro and xenografted in nude mice. Melanoma cells constitutively expressed CXCR1 and CXCR2 mRNA and protein. Highly metastatic A375SM cells expressed higher levels of CXCR1 and CXCR2 mRNA and protein in vitro and in vivo as compared to low metastatic A375P and non-metastatic SBC-2 melanoma cells. Treatment of SBC-2 and A375P cells with exogenously added recombinant IL-8 significantly enhanced their proliferation and invasive potential. Further neutralizing antibodies to CXCR1 and CXCR2 inhibited proliferation and invasive potential of unstimulated and IL-8-stimulated A375P cells. In summary, the data suggest that constitutive expression of CXCR1 and CXCR2 play an important role regulating the IL-8-mediated metastatic phenotype in human malignant melanoma cells.

Animals↗
PubMed2003

Osteocrin, a novel bone-specific secreted protein that modulates the osteoblast phenotype.

Although a number of secreted factors have been demonstrated to be bone regulators, none of these are unique to bone. Using a viral-based signal-trap strategy we have identified a novel gene we have termed "osteocrin." A 1280-bp mRNA encodes osteocrin producing a mature protein of 103 amino acids with a molecular mass of 11.4 kDa. Osteocrin shows no homology with any known gene except for two conserved sequence motifs reminiscent of dibasic cleavage sites found in peptide hormone precursors. Immunofluorescence and Western blot analysis confirmed the secretory nature of osteocrin. Two protein species were identified in the medium of cells overexpressing osteocrin, a full-length 11.4 kDa species and a processed approximately 5 kDa species. Mutation of the 76KKKR79 dibasic cleavage site abolished the appearance of this smaller osteocrin fragment. By in situ hybridization in mouse embryos, osteocrin was expressed specifically in Cbfa-1-positive, osteocalcin-negative osteoblasts. Immunohistochemistry on adult mouse bone showed osteocrin localization in osteoblasts and young osteocytes. By Northern blot analysis, osteocrin expression was only detected in bone, expression peaking just after birth and decreasing markedly with age. In primary osteoblastic cell cultures osteocrin expression coincided with matrix formation then decreased in very mature cultures. Treatment of cultures with 1,25-dihydroxyvitamin D3 resulted in a rapid dose-dependent down-regulation of osteocrin expression, suggesting direct regulation. Chronic treatment of primary cultures with osteocrin-conditioned media inhibited mineralization and reduced osteocalcin and alkaline phosphatase expression. These results suggest that osteocrin represents a novel, unique vitamin D-regulated bone-specific protein that appears to act as a soluble osteoblast regulator.

Amino Acid Sequence↗
PubMed1995

Differential modulation of cell phenotype by different molecular weight forms of basic fibroblast growth factor: possible intracellular signaling by the high molecular weight forms.

To study possible functional differences of the 18-kD and high molecular weight forms of basic fibroblast growth factor (bFGF), we have examined the effect of endogenous production of different bFGF forms on the phenotype of NIH 3T3 cells. Cells transfected with cDNAs coding for either 18-kD bFGF (18-kD bFGF) or all four molecular forms (18, 22, 22.5, 24 kD; wild type [WT] bFGF) exhibit increased migration and decreased FGF receptor number compared to parental cells. However, migration and FGF receptor number of cells transfected with a cDNA coding only for high molecular weight bFGF (22, 22.5, and 24 kD; HMW bFGF) were similar to that of parental cells transfected with vector alone. Cells expressing HMW, 18 kD, or WT bFGF grew to high saturation densities in 10% serum. However, only cells expressing HMW or WT bFGF grew in low serum. Cell surface or metabolic labeling of the different cell types followed by immunoprecipitation with anti-bFGF antibody showed primarily cell surface-associated 18-kD bFGF. In addition, when cells expressing exclusively HMW bFGF were transfected with a cDNA coding for 18-kD bFGF, migration was increased, bFGF receptors were down-regulated, and 18-kD bFGF was found on the cell surface. Cells expressing 18-kD bFGF transfected with a cDNA encoding FGF receptor-2 lacking the COOH-terminal domain (dominant negative bFGF receptor) exhibited a flat morphology and decreases in migration and saturation density. Cells expressing HMW bFGF transfected with the dominant negative bFGF receptor continued to grow to a high saturation density, proliferated in low serum, and exhibited no morphological changes. These results indicate that increased cell migration and FGF receptor down-regulation are mediated by the extracellular interaction of 18-kD bFGF with its cell surface receptor. Growth in low serum may be stimulated by the intracellular action of HMW bFGF through mechanisms independent of the presence of a cell surface receptor. Thus, the different molecular forms of bFGF may act through distinct but convergent pathways.

3T3 Cells↗
PubMed1992

Metabolically-modulated growth and phenotype of the rat heart.

Heart muscle reacts to work overload and various neuroendocrine stimuli by inducing myocyte growth. A novel type of hypertrophy can be induced in the rat heart by etomoxir, which reduces fatty acid oxidation. This hypoglycaemic drug inhibits the mitochondrial carnitine palmitoyltransferase 1, and thus reduces the long-chain fatty acid uptake of mitochondria; in a compensatory manner, the glycolytic flux is enhanced. In rats, etomoxir induced a harmonious growth of the left and right ventricles of normal and pressure-overloaded hearts. To characterize the protein phenotype, myosin expression and sarcoplasmic reticulum (SR) Ca2+ pump activity were determined. In contrast to pressure-overloaded hearts, etomoxir increased the proportion of myosin V1, Ca(2+)-stimulated SR ATPase activity and the rate of SR Ca2+ uptake. Since etomoxir did not increase blood pressure, heart rate or circulating thyroid hormones, it appears that established mechanisms of other models of cardiac hypertrophy were not involved. The etomoxir-induced changes thus seem closely linked to the shift in energy metabolism.

Animals↗
PubMed1991

Effects of interferons on cultured human melanocytes in vitro: interferon-beta but not-alpha or -gamma inhibit proliferation and all interferons significantly modulate the cell phenotype.

The effects of human recombinant interferon-alpha-2a (rIFN-alpha), natural interferon-beta (nIFN-beta) and recombinant interferon-gamma (rIFN-gamma) on the proliferation, morphology and antigen expression of cultured human melanocytes were studied in vitro. The investigations were performed in 12-O-tetradecanoylphorbol-13-acetate (TPA)- and serum-containing melanocyte growth medium (MGM), in TPA- and serum-free complete melanocyte medium (CMM) and its mitogen reduced variant (RMM). In MGM, none of these interferons inhibited the growth of normal melanocytes at concentrations 1-10,000 international units (IU)/ml over a period of 5 d. Only nIFN-beta, dose dependently, inhibited melanocyte proliferation in CMM and RMM in a 6- and 12-d assay (growth inhibition at 10,000 IU/ml; 77-80% of the controls, p less than 0.001). In contrast, rIFN-alpha and rIFN-gamma exerted no (RMM), or minor effects (CMM) on melanocyte proliferation (only in 12-d assays at 10,000 IU/ml: 24% and 21% of the controls respectively, p less than 0.01). In parallel experiments performed on melanoma cells, all three interferons were potent inhibitors of proliferation in a 5-d serum-free assay (growth inhibition at 10,000 IU/ml; rIFN-alpha 59%, nIFN-beta 78%, rIFN-gamma 56%, all p less than 0.001). In addition, nIFN-beta and also rIFN-gamma caused striking morphologic changes of normal melanocytes in vitro. Especially under greater than or equal to 10 IU/ml rIFN-gamma cytoplasmic spreading and flattening of the cultured melanocytes and their nuclei were seen, thus resembling melanoma cells in vitro. Untreated human melanocytes grown in MGM showed high expression of the melanoma-associated antigens HMB-45 (95-100%) and K.1.2 (40-100%), whereas the progression marker A.1.43 was present only on less than 5% of the cells. Cultured melanocytes were 95-100% positive for histocompatibility antigen class I (HLA-I), 30-75% were positive for ICAM-1, whereas they were negative for HLA-DR. After treatment with rIFN-alpha, increased expression of HLA-I antigens was found; nIFN-beta and rIFN-gamma decreased the labeling with HMB-45 (75-100%) and with K.1.2 (25-80%), whereby the expression of A.1.43 was found slightly increased (5-15%). The HLA class I antigens were upregulated by both nIFN-beta and rIFN-gamma, nIFN-beta being the most potent agent. Also, both nIFN-beta and rIFN-gamma increased the expression of ICAM-1 (nIFN-beta, 75-90%; rIFN-gamma, 90-95%) and induced de novo expression of HLA-DR antigen (nIFN-beta, 15-20%; rIFN-gamma, 65-95%).(ABSTRACT TRUNCATED AT 400 WORDS)

Antibodies, Monoclonal↗
PubMed2003

Cadherins as modulators of cellular phenotype.

Cadherins are transmembrane glycoproteins that mediate calcium-dependent cell-cell adhesion. The cadherin family is large and diverse, and proteins are considered to be members of this family if they have one or more cadherin repeats in their extracellular domain. Cadherin family members are the transmembrane components of a number of cellular junctions, including adherens junctions, desmosomes, cardiac junctions, endothelial junctions, and synaptic junctions. Cadherin function is critical in normal development, and alterations in cadherin function have been implicated in tumorigenesis. The strength of cadherin interactions can be regulated by a number of proteins, including the catenins, which serve to link the cadherin to the cytoskeleton. Cadherins have been implicated in a number of signaling pathways that regulate cellular behavior, and it is becoming increasingly clear that integration of information received from cell-cell signaling, cell-matrix signaling, and growth factor signaling determines ultimate cellular phenotype and behavior.

Animals↗
PubMed2003

BMP4 signaling induces senescence and modulates the oncogenic phenotype of A549 lung adenocarcinoma cells.

Lung cancer is the most common visceral malignancy in males, with rapidly increasing incidence in females, and a devastatingly poor prognosis. Transforming growth factor (TGF)-beta has been shown to induce senescence in A549 lung cancer cells, and both TGF-beta and bone morphogenetic protein (BMP) 2 can suppress the transformed phenotype of A549 cells in vitro. We examined the effects of BMP4, another member of the TGF-beta superfamily, on specific oncogenic properties of A549 cancer cells. When A549 cancer cells were treated continuously with 100 ng/ml of BMP4, a senescent phenotype was observed after 2 wk of treatment. The BMP-treated cells appeared larger than untreated cells, grew more slowly, had more senescence-associated beta-galactosidase activity, and had less telomerase activity, as measured by the telomeric repeat amplification protocol assay. Invasion through Engelbreth Holm-Swarm matrix was inhibited in the senescent cell population. Senescent BMP4-treated cells had lower ERK activation, VEGF expression, and Bcl2 expression than wild-type cells, consistent with a less proliferative, less angiogenic phenotype with increased susceptibility to death by apoptosis. BMP4 treatment also resulted in sustained elevation of Smad1. In vivo xenograft studies in the flanks of nude mice confirmed that the BMP-treated cells were significantly less tumorigenic than untreated cells. Direct overexpression of Smad1 using adenoviral constructs resulted in cell death within 5 days. These studies suggest that BMP4 pathway signaling can induce senescence and thus negatively regulate the growth of A549 lung cancer cells.

Adenocarcinoma↗
PubMed2000

Chronic alpha-adrenergic receptor stimulation modulates the contractile phenotype of cardiac myocytes in vitro.

BACKGROUND: Heart failure is characterized by contractile dysfunction of the myocardium and elevated sympathetic activity. We tested the hypothesis that chronic alpha-adrenergic (alpha-ADR) stimulation modifies the molecular and contractile phenotype of cardiac myocytes. METHODS AND RESULTS: Adult rat ventricular myocytes in culture were exposed to alpha-ADR stimulation (norepinephrine + propranolol) for 48 hours. alpha-ADR stimulation decreased the mRNAs for sarcoplasmic reticulum Ca(2+)-ATPase and Ca(2+) release channel by 56% and 52%, respectively, and increased mRNA and protein for the Na(+)-Ca(2+) exchanger by 70% and 39%, respectively. After washout of the alpha-ADR agonist, simultaneous measurement of [Ca(2+)](i) transients with fura 2 and myocyte shortening by video edge-detection showed that [Ca(2+)](i) amplitude and myocyte shortening were decreased in alpha-ADR-treated myocytes, and the time to peak and time from peak to 80% decline of both [Ca(2+)](i) and myocyte shortening were increased. The concentration-response curve for myocyte shortening by the Na(+) channel activator veratridine was shifted leftward in alpha-ADR-stimulated myocytes (EC(50), 21.6+/-4.6 versus 105.8+/-10.5 nmol/L, P:<0.001). CONCLUSIONS: Chronic alpha-ADR stimulation of cardiac myocytes causes decreases in the expression of sarcoplasmic reticulum Ca(2+)-ATPase and the Ca(2+) release channel that are associated with decreases in [Ca(2+)](i) and contractility. alpha-ADR stimulation simultaneously increases Na(+)-Ca(2+) exchanger expression, thereby increasing sensitivity to intracellular Na(+).

Adrenergic alpha-Agonists↗
PubMed2004

Activation of murine macrophages by Neisseria meningitidis and IFN-gamma in vitro: distinct roles of class A scavenger and Toll-like pattern recognition receptors in selective modulation of surface phenotype.

Innate and adaptive immune activation of macrophages (Mphi) by microorganisms and antigen-activated lymphoid cells, respectively, plays an important role in host defense and immunopathology. Antigen-presenting cells express a range of pattern recognition receptors including the class A types I and II scavenger receptors (SR-A) and Toll-like receptors (TLR). Recognition of microbial products by SR-A and TLR controls uptake, killing, altered gene expression, and the adaptive immune response; however, the contribution of each receptor and interplay with cytokine stimuli such as interferon-gamma (IFN-gamma) are not defined. We used Neisseria meningitidis (NM), a potent activator of innate immunity, and IFN-gamma, a prototypic T helper cell type 1 proinflammatory cytokine, to compare surface antigens, secretion of mediators, and receptor functions in elicited peritoneal Mphi from wild-type and genetically modified mouse strains. We show that these stimuli regulate major histocompatibility complex type II (MHC-II) and costimulatory molecules differentially, as well as expression of the mannose receptor and of Mphi receptor with collagenous structure (MARCO), a distinct SR-A, which provides a selective marker for innate activation. In combination, NM inhibited up-regulation of MHC-II by IFN-gamma while priming enhanced release of tumor necrosis factor alpha and nitric oxide. The SR-A contributes to phagocytosis of the organisms but not to their ability to induce CD80, CD86, and MARCO or to inhibit MHC-II. Conversely, studies with lipopolysaccharide (LPS)-deficient organisms and/or TLR-4 mutant mice showed that LPS and TLR-4 are at least partially required to induce CD80, CD86, and MARCO, but LPS is not required to inhibit MHC-II. These studies provide an experimental model and identify surface markers for analysis of innate and acquired immune activation of Mphi.

Animals↗
PubMedDate not supplied

Vasopressin receptors modulate the pharmacological phenotypes of Cushing's syndrome.

We have examined the expression profiles of the different vasopressin receptors (V1, V2, V3) that can be expressed in the three different types of tumors associated with Cushing's syndrome. V3 (V1b) receptor cDNA was cloned from a pituitary tumor responsible for Cushing's disease. We show that it is overexpressed in these tumors and can respond to DD-AVP. High expression of the V3 receptor on highly differentiated, ACTH-secreting, bronchial carcinoid tumors explain why these non-pituitary tumors occasionally respond to vasopressin, mimicking a "pituitary-like" behavior. A retrospective analysis showed that vasopressin induced an ACTH-independent cortisol rise in 27% of the adrenocortical tumors responsible for Cushing's syndrome. V1 mRNA was detected in normal adrenal cortex and in all tumors. Adenomas had significantly higher levels than carcinomas. V1 mRNA levels were higher in responders than in non-responders. One adenoma which had a brisk cortisol response in vivo, also had in vitro cortisol responses that were inhibited by a specific V1 antagonist. In situ hybridization showed the presence of V1 mRNA in the normal human adrenal cortex where the signal predominated in the compact cells of the zona reticularis. A positive signal was also present in the tumors with high V1 mRNA levels determined by RT-PCR; its distribution pattern was heterogeneous and showed preferential association with compact cells. High-and not ectopic-expression of the V1 receptor occurs in a minority of adrenal cortical tumors which become directly responsive to vasopressin stimulation.

Adrenal Cortex Neoplasms↗
PubMed2003

Glanzmann's thrombasthenia: modulation of clinical phenotype by alpha2C807T gene polymorphism.

BACKGROUND AND OBJECTIVES: The expression of Glanzmann's thromboasthenia (GT) varies, even among patients carrying the same mutation. It is conceivable that other gene loci may influence the clinical expression of GT and lead to specific phenotypes. DESIGN AND METHODS: To investigate GT clinical heterogeneity we screened 25 GT patients with a known alpha(IIb)beta3 molecular defect for thrombophilic mutations (FV Leiden, FII A20210) and the platelet glycoprotein (GP) alpha2 C807T gene polymorphism. RESULTS: The FV Leiden mutation was found in 1 patient, the FII A20210 mutation in none. Three GT patients were homozygous for the T807 allele and showed a mild clinical expression of GT whereas none of the patients presenting with a moderate or severe GT phenotype carried the alpha2 TT genotype (p=0.037, two-sided exact test). In patients carrying the same mutation, the clinical GT phenotype was milder in those with the TT807 genotype. INTERPRETATION AND CONCLUSIONS: Since the platelet alpha2 C807T gene polymorphism is associated with alpha2beta1 receptor density on the platelet surface, our findings suggest that the level of alpha2beta1 on platelets may be an additional factor affecting GT clinical expression.

3' Untranslated Regions↗
PubMedDate not supplied

Recombinant interferon alpha-2 modulates hairy cell phenotype "in vitro".

The "in vitro" effect of IFN-alpha on the phenotypic profile of atypical cells from 5 hairy cell leukemia patients was investigated in a 72 hr culture assay. Cytochemical investigations revealed a dramatic decrease in the cytoplasmic content of acid phosphatase and tartrate resistant acid phosphatase in the absence of any apparent morphological modification. Flow cytometry showed that IFN-alpha markedly reduced the density of surface Ig without modifying the original isotype pattern. The expression of the receptor for the Fc fragment of IgG was also reduced. The class II MHC antigen recognized by the monoclonal antibody 12 remained essentially unchanged. Hairy cells were negative for OKT10 and PCA-1 and remained so after IFN-alpha incubation. Present data indicate that IFN-alpha is able to consistently and selectively affect membrane and cytoplasmic features of hairy cells in a short term period. The possibility is envisaged that these changes may be related to the therapeutic efficacy of IFN-alpha.

Adult↗
PubMed1994

[Trials of modulating the MDR1 phenotype in malignant hemopathies].

The first trials with modifier agents and chemotherapy were conducted in myeloma, with verapamil and VAD. The objective responses observed could not be undoubtfully rapported to the addition of modifier agent. The cyclosporin A could be given at 10 to 18 mg/kg/d by IV route during few days, without nephrotoxicity. A bone marrow toxicity was due to the modification of cytostatic pharmacokinetics. The remissions observed with addition of cyclosporin A or quinine in acute leukemia could be due to either the high dose of ara-C given with daunorubicin or mitoxantrone, or to the drug pharmacokinetic modifications, or the P-gp inhibition on leukemic cells (or probably a combination of these factors). Randomized trials are now going on.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Modulation of the phenotype in dominant erythropoietic protoporphyria by a low expression of the normal ferrochelatase allele.

Erythropoietic protoporphyria (EPP) is a monogenic inherited disorder of the heme biosynthetic pathway due to ferrochelatase (FC) deficiency. EPP is generally considered to be transmitted as an autosomal dominant disease with incomplete penetrance, although autosomal recessive inheritance has been documented at the enzymatic and molecular level in some families. In the dominant form of EPP, statistical analysis of FC activities documented a significantly lower mean value in patients than in asymptomatic carriers, suggesting a more complex mode of inheritance. To account for these findings, we tested a multiallelic inheritance model in one EPP family in which the enzymatic data were compatible with this hypothesis. In this EPP family, the specific FC gene mutation was an exon 10 skipping (delta Ex10), resulting from a G deletion within the exon 10 consensus splice donor site. The segregation of all FC alleles within the family was followed using the delta Ex10 mutation and a new intragenic dimorphism (1520 C/T). mRNAs transcribed from each FC allele were then subjected to relative quantification by a primer extension assay and to absolute quantification by a ribonuclease protection assay. The data support the hypothesis that in this family the EPP phenotype results from the coinheritance of a low output normal FC allele and a mutant delta Ex10 allele.

Base Sequence↗
PubMed1998

[Membrane receptors and endocrine tumors: expression of vasopressin receptor V1 modulates the pharmacologic phenotype of adrenocortical tumors].

A retrospective analysis of 26 adrenocortical tumors responsible for Cushing's syndrome showed that vasopressin induced an ACTH-independent cortisol response in seven cases (27%). In comparison 68 of 90 patients with Cushing's disease (76%) had a positive cortisol response. The mRNA for the V1-type vasopressin receptor was detected in normal adrenal cortex and in all tumors, and adenomas had higher levels than carcinomas. One adenoma which had a brisk cortisol response in vivo, also had in vitro cortisol responses that were inhibited by a specific V1 antagonist. In situ hybridization showed the presence of V1 mRNA in the normal and tumoral adrenal cortex. We conclude that the vasopressin V1 receptor gene is expressed in normal and tumoral adrenocortical cells. High--and not ectopic--expression occurs in a minority of tumors which become directly responsive to vasopressin stimulation.

Adrenal Gland Neoplasms↗