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Biomedical subjects

L M Shulman

Publications and source records attributed to L M Shulman.

At least 55 records · Page 3Linked to original sources
PubMed1995

The plasmacytoma growth inhibitor restrictin-P is an antagonist of interleukin 6 and interleukin 11. Identification as a stroma-derived activin A.

A stromal protein, designated restrictin-P, that specifically kills plasma-like cells was purified to homogeneity and shown to be identical with activin A. The specificity to plasma-like cells stemmed from the ability of restrictin-P/activin A to competitively antagonize the proliferation-inducing effects of interleukin (IL) 6 and IL-11. Restrictin-P further interfered with the IL-6-induced secretion of acute phase proteins by HepG2 human hepatoma cells and with the IL-6-mediated differentiation of M1 myeloblasts. A competition binding assay indicated that restrictin-P did not interfere with the binding of IL-6 to its receptor on plasma-like cells, suggesting that it may act by intervening in the signal transduction pathway of the growth factor. Indeed, concomitant addition of restrictin-P and IL-6 to cytokine-deprived B9 hybridoma cells was followed by sustained overexpression of junB gene until cell death occurred, while IL-6 alone caused a transient increase only. This altered response to IL-6 stimulation was accompanied by a moderate increase in STAT protein activation. Thus, in this study, we identified the plasmacytoma growth inhibitor, restrictin-P, as being activin A of stromal origin. It is shown that activin A is an antagonist of IL-6-induced functions and that it modifies the IL-6 signaling pattern.

Activins↗
PubMed1995

Distribution of both rotavirus VP4 genotypes and VP7 serotypes among hospitalized and nonhospitalized Israeli children.

Human rotaviruses belonging to genotype P9, of probable feline origin, which included both G3 and G1 serotypes, were detected in 3.8% of children shedding rotaviruses who attended sick fund clinics throughout Israel. None were detected in children admitted to hospitals because of severe diarrhea. In contrast, the relative prevalences of genotypes P8 and P4 were similar between the two groups.

Animals↗
PubMed1995

Psychosis as the initial manifestation of adult-onset Niemann-Pick disease type C.

Niemann-Pick disease type C (NPC) is a neurometabolic genetic disorder that is distinguished from Niemann-Pick disease by its later onset, more insidious progression, variable visceromegaly, and abnormalities of intracellular cholesterol metabolism. We describe a patient who presented with an 8-year history of psychosis requiring chronic neuroleptic therapy for a presumed diagnosis of schizophrenia. He was subsequently diagnosed with NPC as the emerging features of dementia, ataxia, dysarthria, and vertical supranuclear ophthalmoplegia were recognized. The characteristic features of adult-onset NPC and the obstacles to early diagnosis are reviewed.

Adult↗
PubMed1994

Differential tyrosine phosphorylation of the IFNAR chain of the type I interferon receptor and of an associated surface protein in response to IFN-alpha and IFN-beta.

The human interferon alpha-receptor (IFNAR gene product) is a transmembranal protein of 557 amino acids with an intracytoplasmic domain of 100 amino acids containing four tyrosines. Antibodies to a C-terminal peptide (residues 521-536) were developed which efficiently immunoprecipitate the 105 kDa IFNAR protein from detergent extracts of human cells. We show that the IFNAR protein becomes tyrosine phosphorylated within 5 min after treatment of human myeloma U266 cells with IFN-alpha 2, IFN-alpha 8 or IFN-beta. The IFNAR chain interacts with both IFN-alpha 2 and IFN-beta, as demonstrated by cross-linking. Among elements involved in signal transduction by type I IFNs, the tyrosine kinase Tyk2 but not Jak1, and the ISGF3 transcription factor subunit Stat2 (p113) but not Stat1 (p91), are found associated with the IFNAR protein. After IFN-beta treatment for 5 min, a tyrosine-phosphorylated protein of approximately 95 kDa (beta-PTyr) is found bound to IFNAR, but can be dissociated by denaturation. The beta-PTyr protein is present on the cell surface, like IFNAR, as shown by extracellular biotin tagging. The ratio of beta-PTyr to IFNAR tyrosine phosphorylation is much higher with IFN-beta than with IFN-alpha 2 or 8. Both are IFN dependent and abrogated by a monoclonal antibody which blocks IFNAR action. The beta-PTyr component may represent an important difference in the action of IFN-beta as compared with IFN-alpha in their shared receptor system.

Amino Acid Sequence↗
PubMed1994

Differential responses of fetal, neonatal, and adult myelopoietic progenitors to interferon and tumor necrosis factor.

Human fetal liver (FL) and neonatal cord blood (CB) granulocyte-monocyte colony-forming progenitor cells (GM-CFC) are unique in their physiological environment and in certain proliferative and differentiative capacities. Tumor necrosis factor (TNF) and interferon (IFN) may inhibit or stimulate the growth of human bone marrow GM-CFC in vitro. The effects of recombinant human (rh) TNF-alpha, rhIFN-alpha, and rhIFN-tau on recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF)-stimulated clonogenic cultures of day 7 GM-CFC from FL and umbilical CB were compared with rhGM-CSF-stimulated GM-CFC from normal human bone marrow (BM). We demonstrate that, in comparison to BM progenitor cells, GM-CFC from both FL and CB were highly resistant to growth inhibition by all three cytokines. Furthermore, clonogenic growth of progenitors from FL and CB was markedly potentiated by IFN-tau in GM-CSF-stimulated cultures and was stimulated by IFN-tau in the absence of GM-CSF. Depletion of potential accessory cells resulted in a marked stimulatory response of CB cells to TNF-alpha, in the presence of GM-CSF, while it did not alter the responses to IFN. The stimulatory effects of IFN-tau and TNF-alpha may be indirectly mediated, at least in part, through induction of increased GM-CSF production and increased GM-CSF receptor expression by fetal cells. Divergent responses of myelopoietic cells, derived from various hematopoietic compartments, to regulatory actions of cytokines may provide a basis for further understanding the role of the environment in maturation and differentiation of granulocytes and monocytes.

Adult↗
PubMed1993

Combined therapy with IL-6 and inactivated tumor cells suppresses metastasis in mice bearing 3LL lung carcinomas.

We investigated the anti-tumor effects of human recombinant interleukin-6 (hrIL-6) on the highly metastatic Lewis lung-carcinoma clone, D122. These cells express high-affinity IL-6 receptors at numbers comparable to the IL-6-dependent murine hybridoma B9 cells; however, IL-6 did not affect D122 cell proliferation or expression of MHC-class-I antigens in vitro. In vivo, treatment of mice bearing D122 tumors in the footpads, with a low dose of IL-6 in 3 daily injections, 4 days a week for 3 weeks, significantly decreased spontaneous metastases. However, only combined treatment of IL-6 and irradiated tumor cells resulted in almost complete protection against spontaneous metastases. Histological analysis confirmed the absence of micrometastases in most of the animals treated by this combination protocol. Analysis of the cytolytic activity of splenocytes at various time points during combined IL-6 and immunotherapy of tumor-bearing mice revealed significant and sustained lysis of the poorly immunogenic D122 carcinoma cells, while splenocytes of control mice could not lyse D122 target cells. Activation of specific immunity was also demonstrated when mice were pre-immunized with hrIL-6 and inactivated D122 cells and challenged with live carcinoma cells 10 days later. Significant growth inhibition of the primary tumor was observed.

Animals↗
PubMed1993

Glycerol induced ARF in rats is mediated by tumor necrosis factor-alpha.

Glycerol-induced acute renal failure (ARF) in rats is a model of acute trauma in which intra-muscular injection of 50% glycerol causes rapid myoglobinuria, oliguria, and a rapid reduction in glomerular filtration rate. We found that plasma tumor necrosis factor-alpha (TNF-alpha) is rapidly induced in glycerol injected rats. It can be detected in some animals as early as 30 minutes post-injection, peaks at one hour (range: 4 to 32 U/ml) with no significant difference between blood from renal vein and vena cava, and decreases by three hours. None was detected in control saline injected rats (P < 0.001). Four out of five rats infused with neutralizing anti-TNF-alpha antiserum (200 microliters/300 g body wt) immediately prior to glycerol injection had significantly protected kidney function (P = 0.001). In these rats, plasma urea (104.8 +/- 58.9 mg%) and creatinine (1.16 +/- 0.38 mg%) were lower and creatinine clearance higher (0.34 +/- 011 ml/min) than in glycerol injected animals pretreated with normal serum (291.8 +/- 41.8 mg%, 3.15 +/- 0.74 mg%, and 0.03 +/- 0.03 ml/min, respectively) or animals injected with glycerol alone (302.6 +/- 76.8 mg%, 3.45 +/- 0.97 mg%, and 0.03 +/- 0.03 ml/min, respectively). These results imply a direct role for TNF-alpha in pathogenesis of glycerol induced ARF in rats.

Acute Kidney Injury↗
PubMed1993

Abrogation of B16 melanoma metastases by long-term low-dose interleukin-6 therapy.

We investigated the antitumor effects of human recombinant interleukin-6 (hrIL-6) on the highly metastatic B16 melanoma clone F10.9. These tumor cells were found to have very low levels of IL-6 receptors and in vitro IL-6 had no effect on cell proliferation or on the expression of MHC class I antigens. However, in vivo IL-6 was active against the metastatic growth of this tumor in mice, presumably through indirect immune effects. Low-dose IL-6 (1-10 micrograms/day), in three daily injections, 4 days a week, for 3 weeks, strongly inhibited the formation of experimental lung metastases following intravenous tumor cell inoculation. IL-6 therapy could be started even 10 days after tumor injection, when metastases are already established. Moreover, IL-6 treatment of mice bearing F10.9 tumors in the footpads resulted in complete protection against pulmonary spontaneous metastasis and in long-term survival. Histology confirmed the absence of micrometastases in most of the IL-6-treated animals. Analysis of the cytolytic activity of splenocytes at different times during therapy of tumor-bearing mice revealed significant lysis (up to 42%) of the melanoma F10.9 cells in the mice receiving IL-6 but not in the control mice.

Animals↗
PubMed1992

Enhancement of interleukin 6 cytostatic effect on human breast carcinoma cells by soluble IL-6 receptor from urine and reversion by monoclonal antibody.

Interleukin 6 receptor soluble urinary protein (IL-6-R-SUP), a purified urinary protein binding IL-6 and identified as a truncated 50 kDa soluble form of the 80 kDa IL-6 cellular receptor, was tested for its biological activity. Addition of IL-6-R-SUP enhances the growth stimulation of mouse plasmacytoma T1165 by subliminal concentrations of human recombinant IL-6. Since this effect could be due to a lower affinity of human IL-6 for the mouse cell receptor, we tested the effect of IL-6-R-SUP on human cells. We show that the growth-inhibitory effect of IL-6 on breast carcinoma cells is enhanced by addition of IL-6-R-SUP to these human cells although they possess abundant IL-6 receptors. With IL-6-R-SUP, complete growth inhibition by IL-6 could be achieved and the cells became more sensitive to low levels of IL-6. These effects were prevented by a monoclonal antibody against IL-6-R-SUP which blocks IL-6 binding to cells. The naturally occurring IL-6-R-SUP may help to increase the growth-regulatory action of IL-6.

Animals↗
PubMed1992

Detection of CMV-DNA in cells from peritoneal fluid of IPD/CAPD patients by polymerase chain reaction.

Documented viral peritonitis in peritoneal dialysis patients is rare, although up to 20% of all cases are culture negative (non-fungal, non-bacterial). CMV-infected peritoneal cells may serve as a reservoir for reinfection and/or reactivation of CMV after renal transplantation. CMV-Polymerase Chain Reaction (CMV-PCR) amplification analysis identified CMV-DNA in cells from the peritoneal dialysate of 8 patients (3 culture negative peritonitis from a total of 5 examined) and 5 asymptomatics) out of 17 potential kidney transplant recipients (6 on IPD 16.6 +/- 6 months, range 10-29 months; 11 on CAPD 28.1 +/- 25 months, range 2-81 months). Serum titers (10/17 patients analyzed) of anti-CMV IgG antibodies ranged from < 1:20 to 1:320 (no correlation with CMV-DNA) while anti-CMV IgM antibodies were undetectable. Detection of CMV specific sequences in peritoneal cells in peritoneal dialysis patients by the PCR assay is sensitive (amplification of a 133 bp immediate early CMV gene sequence allows detection of 10 CMV infected cells in a background of 10(5) uninfected peritoneal cells), rapid (1 day visual, 3 days with confirmation by Southern hybridization), specific (no amplification of human embryo and kidney cell DNA, or HSV, EBV, or VZV infected cells) and is non-invasive in IPD/CAPD patients since no additional invasive technique is required.

Cytomegalovirus↗
PubMed1984

Assignment of low-molecular-weight human (2', 5')A synthetase to chromosome 11.

Human low-molecular-weight (2', 5')A synthetase is induced in certain human X mouse somatic hybrid cell lines when these cells are treated with mouse interferon. We have assigned the gene coding for this interferon-inducible antiviral enzyme to human chromosome 11 by somatic cell genetic techniques (1). Fluorescence-activated cell sorting for cells expressing or lacking 4F2 antigen in two independently derived, chromosome 11-containing hybrid cell lines separated the cells into subpopulations of cells that had retained or segregated chromosome 11, respectively (2). We used these subpopulations to confirm our gene assignment by demonstrating that retention of chromosome 11 was required for expression of human (2', 5')A synthetase.

2',5'-Oligoadenylate Synthetase↗
PubMed1984

Antibodies to chromosome 21 coded cell surface components block binding of human alpha interferon but not gamma interferon to human cells.

Antisera raised against a human X mouse hybrid cell line containing human chromosome 21 as its only human chromosome, block induction of an antiviral state by human alpha interferon (IFN-alpha), block induction of (2'-5')oligoisoadenylate synthetase [2'-5')A synthetase), and block binding of 125I-labeled and 35S-labeled recombinant, human IFN-alpha A, but not 125I-labeled IFN-gamma, to cell surface receptors. The data presented clearly demonstrate that the cell surface receptors for IFN-alpha and IFN-gamma are different, and provide independent evidence of the role of a chromosome 21 coded cell surface molecule in the pathway to the generation of the antiviral state.

2',5'-Oligoadenylate Synthetase↗