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Biomedical subjects

D Aderka

Publications and source records attributed to D Aderka.

At least 37 records · Page 2Linked to original sources
PubMed1993

Differential regulation of tumour necrosis factor receptors (TNF-R) by IL-4; upregulation of P55 and P75 TNF-R on synovial joint mononuclear cells.

Interleukin 4 (IL-4) has previously been shown to downregulate the production of proinflammatory cytokines such as TNF-alpha, and hence has been considered to be a potential anti-inflammatory agent. In this study we have investigated the effects of IL-4 on the expression of both p55 and p75 TNF receptors (TNF-R) by flow cytometry and radioligand binding analyses and demonstrate that IL-4 downregulates both p55 and p75 TNF-R on HeLa and Jijoye cell lines in a dose dependent manner. IL-4 reduced the number of p55 TNF-R on HeLa cells from 6400 (Kd 5.1 nM) to 3900 (Kd 3.7 nM), and p75 TNF-R on Jijoye cells from 4800 (Kd 1.6 nM) to 3250 (Kd 1.5 nM). However, different effects were observed on peripheral blood mononuclear cells (PBMC). IL-4 inhibited the increase in p55 and p75 TNF-R on PBMC following adherence, whereas IL-4 upregulated p75 TNF-R expressed on PHA induced T cell blasts. To assess further the possible anti-inflammatory properties of IL-4, we studied its effects on synovial joint mononuclear cell cultures from 15 patients with inflammatory synovitis. In contrast to the differential effects of IL-4 on monocytes and T cells, IL-4 upregulated both p55 (P < 0.05) and p75 TNF-R (P < 0.005) on synovial joint cells in culture. IL-4 treatment caused a small decrease in levels of bioactive TNF-alpha in RA synovial culture supernatants, together with an increase in soluble p75 TNF-R levels although differences were not significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Arthritis↗
PubMed1993

Circulating plasma receptors for tumour necrosis factor in Malawian children with severe falciparum malaria.

Tumour necrosis factor (TNF) concentrations are increased in the plasma during a malarial illness, and are highest in patients with severe or fatal disease. We have studied the plasma concentrations of two soluble receptors (sTNF-R1 and sTNF-R2), which act as binding proteins for TNF, in children with falciparum malaria. In 52 Malawian children with malaria, plasma concentrations of both sTNF-R1 (mean (S.D.) 4759(2552) pg/ml) and sTNF-R2 (59077(37102) pg/ml) were greatly increased when compared with levels of convalescence (sTNF-R1 718(68), and sTNF-R2 8015(7021) pg/ml), and in controls without malaria (486(1353) and 4380(2168)). Concentrations of both receptors correlated with plasma levels of TNF measured by immunoradiometric assay, but not with those of another cytokine, IL-6. The mean plasma concentrations of both immunoreactive TNF and soluble TNF receptors were greater in patients with cerebral malaria than those with uncomplicated malaria. Despite high levels of immunoreactive TNF in the plasma of patients acutely ill with malaria, no bioactive TNF could be detected in these patients by the WEHI cell bioassay. Soluble TNF receptors are present in greatly increased concentrations in the plasma of patients with malaria and may play a role in mediating or modulating the pathogenetic effects of the cytokine.

Child↗
PubMed1993

Soluble tumor necrosis factor receptor expression in patients with metastatic renal cell carcinoma treated with interleukin-2-based immunotherapy.

Two distinct types of soluble tumor necrosis factor alpha receptors (sTNFRs), which are felt to represent proteolytic cleavage products of the extracellular domains of membrane-bound TNFRs of molecular mass, 55 and 75 kDa, are found in the serum and urine of humans. We have measured the serum concentrations of these receptors in eight patients with metastatic renal cell carcinoma during treatment with interleukin-2 (IL-2)-based immunotherapy. The mean pretreatment concentration of sTNFR-55 kDa (p < 0.05) but not sTNFR-75 kDa was significantly elevated prior to the onset of immunotherapy. In one patient the concentrations of both sTNFRs decreased dramatically following removal of the primary tumor. There were significant increases in the concentrations of both sTNFRs in patients treated with IL-2-based therapy that included in vivo primed tumor infiltrating lymphocytes (pTILs); some of these patients eventually achieved a complete response to therapy. These data demonstrate that sTNFR-55 kDa is elevated in patients with metastatic renal cell carcinoma prior to therapy and that IL-2-based therapy that included pTIL cells results in a further increase in sTNFRs.

Carcinoma, Renal Cell↗
PubMed1993

Extracellular matrix induces tumour necrosis factor-alpha secretion by an interaction between resting rat CD4+ T cells and macrophages.

T lymphocytes and macrophages (M phi) have been seen to accumulate at sites of lesions in blood vessel walls, suggesting that these cells may contribute to the pathogenesis of inflammatory reactions. Tumour necrosis factor-alpha (TNF-alpha), a cytokine produced by both M phi and T lymphocytes, plays a major role in inflammatory reactions, blood vessel formation, thrombosis and atherosclerosis. We now report that secretion of TNF-alpha by cloned CD4+ rat T cells, and to a lesser degree by peripheral T cells, and M phi can be induced in vitro in the absence of antigen, in a major histocompatibility complex (MHC) class II-independent manner by integrin-mediated recognition of immobilized components of extracellular matrix such as fibronectin and laminin; the secretion of TNF-alpha by the interacting resting cells on fibronectin was partially abrogated by the presence of the Arg-Gly-Asp (RGD)-containing amino acid sequence. This T cell-M phi interaction involves CD2 and CD4 molecules and requires a signal transduced in the T cells by a protein tyrosine kinase. Thus, a multicellular interaction with extracellular matrix protein exposed as a consequence of vascular wall injury can serve to signal the secretion of TNF-alpha which induces the recruitment of additional immune cells to the developing lesion.

Animals↗
PubMed1992

Stabilization of the bioactivity of tumor necrosis factor by its soluble receptors.

The receptors for tumor necrosis factor (TNF) exist in cell-associated as well as soluble forms, both binding specifically to TNF. Since the soluble forms of TNF receptors (sTNF-Rs) can compete with the cell-associated TNF receptors for TNF, it was suggested that they function as inhibitors of TNF activity; at high concentrations, the sTNF-Rs indeed inhibit TNF effects. However, we report here that in the presence of low concentrations of the sTNF-Rs, effects of TNF whose induction depend on prolonged treatment with this cytokine are augmented, reflecting an attenuation by the sTNF-Rs of spontaneous TNF activity decay. Evidence that this stabilization of TNF activity by the sTNF-Rs follows from stabilization of TNF structure within the complexes that TNF forms with the sTNF-Rs is presented here, suggesting that the sTNF-Rs can affect TNF activity not only by interfering with its binding to cells but also by stabilizing its structure and preserving its activity, thus augmenting some of its effects.

Cell Count↗
PubMed1992

Increased levels of soluble tumor necrosis factor receptors in the sera and synovial fluid of patients with rheumatic diseases.

OBJECTIVE: Recently, 2 classes of cytokine inhibitors have been defined at the molecular level. The largest group comprises the extracellular domains of cell surface cytokine receptors, and includes both tumor necrosis factor receptors (TNF-R). The present study was conducted to investigate the role of TNF inhibitors in arthritis. METHODS: We measured p55 and p75 soluble TNF-R (sTNF-R) in serum and synovial fluid (SF) samples from patients with rheumatic diseases and compared their levels with levels of soluble interleukin-2 receptors (sIL-2R). Sensitive enzyme-linked immunosorbent assays (ELISA), specific for p55 and p75 sTNF-R and for sIL-2R, were used. RESULTS: Serum levels of p75 sTNF-R were 3-4-fold higher than levels of p55 sTNF-R, and both were significantly elevated in patients with osteoarthritis (OA) and rheumatoid arthritis (RA) compared with healthy controls. RA SF levels of sTNF-R were 4-5-fold higher than levels in serum, suggesting local production in the joint, and were significantly higher than levels in the SF of patients with seronegative arthropathy or OA. Furthermore, levels of p55 and p75 sTNF-R, but not sIL-2R or TNF alpha measured by ELISA, were increased in the SF of patients with clinically active RA. The soluble TNF-R in RA and OA SF were functional since they inhibited TNF activity in a cytotoxicity assay in proportion to the levels of inhibitor present. Evaluation of serially obtained serum samples suggested that sTNF-R may be a useful parameter for monitoring RA disease activity. CONCLUSION: Biologically active soluble TNF-R are up-regulated in patients with rheumatic disease and are produced locally in the joints. Measurement of serum levels of TNF-R may be useful for monitoring of disease, and determination of SF levels could be of diagnostic value.

Adult↗
PubMed1992

Induction of soluble tumour necrosis factor receptors during treatment with interleukin-2.

Interleukin-2 (IL-2) treatment induces other cytokines such as tumour necrosis factor (TNF) TNF may mediate some of the anti-tumour activity of IL-2, but conversely, may contribute to its dose limiting toxicities. Cleaved extracellular domains of the p55 and the p75 TNF receptors (sTNF-R1 and R2) bind to and inhibit the biological activity of TNF in vitro, but may also act as carrier molecules. We have assayed TNF and sTNFR-1 and 2 in the plasma of advanced cancer patients, before and during treatment with IL-2. Plasma levels of TNF in 22 patients were not significantly different from 25 normal controls, but levels of sTNFR-1 and sTNFR-2 were higher (P < 0.001). Levels of TNF and both its soluble receptors were significantly increased in 13 patients receiving IL-2 therapy. Maximum induced levels of sTNFR-1 and sTNFR-2 correlated closely with maximum induced levels of TNF (P < 0.001), but peak levels of sTNFR-1 and two were achieved 24-48 h after peak TNF. Levels of TNF and sTNF-Rs did not correlate with toxicity. Treatment with IL-2 leads not only to induction of TNF but also soluble binding proteins at levels which may modulate its biological activity.

Breast Neoplasms↗
PubMed1992

Erythropoietin therapy obviates the need for recurrent transfusions in a patient with severe hemolysis due to prosthetic valves.

Erythropoietin has been proved extremely effective in ameliorating the anemia of chronic renal failure and is currently under intensive investigation. We describe a patient with severe anemia and secondary hemochromatosis due to prosthetic valves, who has been successfully treated with erythropoietin. During 12 months' follow-up, an acceptable hemoglobin level was maintained without any need for blood transfusions; in addition, there was evidence indicating regression of hemochromatosis. This patient illustrates that erythropoietin therapy might prove beneficial for similar cases.

Anemia, Hemolytic↗
PubMed1992

Variation in serum levels of the soluble TNF receptors among healthy individuals.

Soluble forms of the two receptors for tumor necrosis factor (TNF) are present in human sera at concentrations that increase greatly in various disease states as well as varying among healthy individuals. Measurements of the soluble TNF receptor (sTNF-R) concentrations in healthy individuals at time lapses of 3 months (17 individuals) or 1 year (51 individuals) showed a significant correlation between the first and the second measurements from each individual, implying that individual differences are stable. Since the sTNF-Rs are believed to function as physiological attenuators of TNF activity, these steady individual differences may contribute to differences in the severity of the harmful effects of TNF in disease states.

Enzyme-Linked Immunosorbent Assay↗
PubMed1991

Increased serum levels of soluble receptors for tumor necrosis factor in cancer patients.

Soluble forms of the two molecular species of the cell surface receptors for tumor necrosis factor (TNF) have been detected in normal urine. Using enzyme-linked immunosorbent assays for these soluble receptors, we determined their levels in the sera of 40 healthy subjects and 59 patients with solid tumors. The mean +/- SD concentrations of both the soluble type I (p55) and type II (p75) receptors were significantly higher in the cancer patients than in the healthy controls: 1.96 +/- 1.19 versus 0.79 +/- 0.19 ng/ml (P less than 0.001) and 6.43 +/- 4.8 versus 3.2 +/- 0.6 ng/ml (P less than 0.001), respectively. The incidence and the extent of the increase correlated with the staging of disease. Sera of the cancer patients had a marked inhibitory effect on the in vitro cytocidal activity of TNF. This inhibition was proportional to the content of soluble TNF receptors and could be fully abolished by the addition to the sera of specific antibodies against the receptors. Among the cancer patients, the incidence of increase in the concentrations of soluble TNF receptors (about 70%) greatly exceeded that of the serum carcinoembryonic antigen (about 26%), a commonly used cancer marker. The origin of the serum soluble TNF receptors in cancer patients and the physiological implications of their effect on TNF function remain to be elucidated.

Adult↗
PubMed1991

Is idiopathic atrial fibrillation caused by occult thyrotoxicosis? A study of one hundred consecutive patients with atrial fibrillation.

In this study we evaluated the possible relationship between idiopathic atrial fibrillation and occult thyrotoxicosis, diagnosed by lack of response of thyroid stimulating hormone to administration of thyrotropin releasing hormone. Three groups were compared: 25 patients with idiopathic atrial fibrillation; 52 with cardiovascular atrial fibrillation; and 27 with sinus rhythm. Patients were excluded with any clinical evidence of thyrotoxicosis or with elevated serum FT4 level, as well as those with diseases or on medications known to be associated with a diminished response to administration of the releasing hormone. A flat test (lack of response) was found in only 4% of the patients. There was no significant difference among the 3 groups. Based on these data we believe that there is no relationship between idiopathic atrial fibrillation or any other type of atrial fibrillation and occult thyrotoxicosis.

Adult↗
PubMed1991

Budd-Chiari syndrome in Israel: predisposing factors, prognosis, and early identification of high-risk patients.

In twenty-seven patients with venography-documented Budd-Chiari syndrome (BCS), underlying diseases included polycythemia vera (nine patients), membranous occlusion of the inferior vena cava (three), and cirrhosis (two). In only nine patients did the syndrome occur in the absence of any predisposing factor. All patients with a membranous web were relatively young (mean age 29 years) and were born in Morocco. With regard to prognosis, three groups could be delineated. Eight patients formed a rapidly progressive group, with mean survival from first symptom of only 4.3 weeks, and were characterized mainly by their relatively advanced age and minimal enlargement of the spleen.

Adult↗
PubMed1991

Soluble and cell surface receptors for tumor necrosis factor.

Tumor necrosis factor (TNF) initiates its multiple effects on cell function by binding at a high affinity to specific cell surface receptors. Two different molecular species of these receptors, which are expressed differentially in different cells, have been identified. The cDNAs of both receptors have recently been cloned. Antibodies to one of these receptor species (the p55, type I receptor) can trigger a variety of TNF like effects by cross-linking of the receptor molecules. Thus, it is not TNF itself but its receptors that provide the signal for the response to this cytokine. The intracellular domains of the two receptors differ in structure, suggesting that they mediate different activities. Their extracellular domains, however, are structurally related. Both contain cysteine-rich repeats which are homologous to repeated structures found in the extracellular domains of the nerve growth factor receptor and the CDw40 protein. Truncated soluble forms of the two receptors, corresponding to these cysteine-rich repeated structures, have been detected in human urine and were later found to be present also in the serum. The serum levels of those soluble TNF receptors increase dramatically in certain pathological situations. Release of the soluble receptors from the cells seems to occur by proteolytic cleavage of the cell surface forms and appears to be a way of down-regulating the cell response to TNF. Because of their ability to bind TNF, the soluble receptors exert an inhibitory effect on TNF function, and may thus act as physiological attenuators of its activity.

Animals↗
PubMed1991

Role of tumor necrosis factor in the pathogenesis of intravascular coagulopathy of sepsis: potential new therapeutic implications.

Tumor necrosis factor (TNF) induced by bacterial lipopolysaccharide (LPS) was shown to have an important role in precipitation of septic shock and disseminated intravascular clotting (DIC). At the endothelial level TNF down-regulates thrombomodulin (thus preventing protein C formation) and inhibits the production of tissue plasminogen activator (t-PA), thus impairing anticoagulant mechanisms. On the other hand, TNF up-regulates the production of procoagulant factors such as t-PA inhibitor (PAI), tissue factor and platelet activating factor (PAF). These effects create an imbalance between procoagulant and anticoagulant mechanisms, in favor of the former. TNF also activates polymorphonuclears (PMNs), and increases their chemotaxis and adherence to endothelial surfaces by up-regulation of specific endothelial (ELAM-1) and PMN (CDw18) adherence proteins. The damage inflicted by activated PMN to the endothelial cell promotes tissue factor exposure and PAI release, with initiation of the characteristic explosive coagulation process of DIC, facilitated by the dissociation between pro- and anticoagulant mechanisms induced by TNF. These newly discovered mechanisms precipitating septic shock and DIC enable consideration of new treatments for this condition as anti-TNF antibodies or TNF inhibitors, anti-ELAM-1 antibodies anti-tissue factor antibodies, administration of activated factor C, etc. These therapeutic approaches may revolutionize the treatment of septic shock and DIC in the next decade.

Animals↗
PubMed1990

Soluble forms of tumor necrosis factor receptors (TNF-Rs). The cDNA for the type I TNF-R, cloned using amino acid sequence data of its soluble form, encodes both the cell surface and a soluble form of the receptor.

Two proteins which specifically bind tumor necrosis factor (TNF) have recently been isolated from human urine in our laboratory. The two proteins cross-react immunologically with two species of cell surface TNF receptors (TNF-R). Antibodies against one of the two TNF binding proteins (TBPI) were found to have effects characteristic of TNF, including stimulating phosphorylation of specific cellular proteins. Oligonucleotide probes designed on the basis of the NH2-terminal amino acid sequence of TBPI were used to clone the cDNA for the structurally related cell surface type 1 TNF-R. It is notable that although this receptor can signal the phosphorylation of cellular proteins, it appears from its amino acid sequence to be devoid of intrinsic protein kinase activity. The extracellular domain of the receptor is composed of four internal cysteine-rich repeats, homologous to structures repeated four times in the extracellular domains of the nerve growth factor receptor and the B lymphocytes surface antigen CDw40. The amino acid composition and size of the extracellular domain of the type I TNF-R closely resemble those of TBPI. The COOH-terminal amino acid sequence of the four cysteine rich repeats within the extracellular domain of the type I TNF-R matches the COOH-terminal sequence of TBPI. Amino acid sequences in the extracellular domain also fully match other sequences found in TBPI. On the other hand, amino acid sequences in the soluble form of the type II TNF-R (TBPII), while indicating a marked homology of structure, did not suggest any identity between this protein and the extracellular domain of the type I TNF-R. CHO cells transfected with type I TNF-R cDNA produced both cell surface and soluble forms of the receptor. The receptor produced by CHO cells was recognized by several monoclonal antibodies against TBPI, reacting with several distinct epitopes in this molecule. These data suggest that the soluble forms of the TNF-Rs are structurally identical to the extracellular cytokine binding domains of these receptors and are consistent with the notion that the soluble forms are, at least partly, derived from the same transcripts that encode the cell surface receptors.

Amino Acid Sequence↗