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R Neta

Publications and source records attributed to R Neta.

At least 19 recordsLinked to original sources
PubMed2002

Developing additional resources.

We briefly outline existing information about several cohorts in the Southern Urals, Semipalatinsk and the Altai regions, in addition to those discussed in the companion papers in this issue of Radiation and Environmental Biophysics. These include: (a) the East-Urals Radiation Trace (EURT) cohort of individuals (exposed to fallout from the September 1957 explosion of a storage tank containing liquid radioactive waste from the Mayak Production Association) as well as their offspring, (b) the cohort of exposed parents (i.e. workers of the Mayak facility) and their children, having been established with the aim of examining reproductive health, and (c) several additional cohorts in the Altai region and in Semipalatinsk, where investment of additional resources would greatly facilitate the progress of ongoing studies. Furthermore, we include a brief description of the Russian Human Radiobiology Tissue Repository, which has been established in the city of Ozyorsk and is in the process of making an inventory of autopsied tissues from 700 deceased Mayak workers and of collecting and storing donations of blood and tumor tissues from the members of the Mayak workers cohort currently residing in the city.

Cohort Studies↗
PubMed2000

The promise of molecular epidemiology in defining the association between radiation and cancer.

Molecular epidemiology involves the inclusion in epidemiologic studies of biologic measurements made at a genetic and molecular level and aims to improve the current knowledge of disease etiology and risk. One of the goals of molecular epidemiology studies of cancer is to determine the role of environmental and genetic factors in initiation and progression of malignancies and to use this knowledge to develop preventive strategies. This approach promises extraordinary opportunities for revolutionizing the practice of medicine and reducing risk. However, this will be accompanied by the need to address and resolve many challenges, such as ensuring the appropriate interpretation of molecular testing and resolving associated ethical, legal, and social issues. Traditional epidemiologic approaches determined that exposure to ionizing radiation poses significantly increased risk of leukemia and several other types of cancer. Such studies provided the basis for setting exposure standards to protect the public and the workforce from potentially adverse effects of ionizing radiation. These standards were set by using modeling approaches to extrapolate from the biological effects observed in high-dose radiation studies to predicted, but mostly unmeasurable, effects at low radiation doses. It is anticipated that the addition of the molecular parameters to the population-based studies will help identify the genes and pathways characteristic of cancers due to radiation exposure of individuals, as well as identify susceptible or resistant subpopulations. In turn, the information about the molecular mechanisms should aid to improve risk assessment. While studies on radiogenic cancers are currently limited to only a few candidate genes, the exponential growth of scientific knowledge and technology promises expansion of knowledge about identity of participating genes and pathways in the future. This article is meant to provide an introductory overview of recent advances in understanding of carcinogenesis at the molecular level, with an emphasis of the aspects that may be of use in establishing the association between radiation and cancer.

Cell Cycle↗
PubMed1997

Modulation of radiation damage by cytokines.

Cytokines, hormone-like proteins that are produced by stimulated cells and tissues, serve as intercellular messengers. The production of an expanding number of recombinant cytokines in pharmacological quantities has permitted an assessment of the benefit they may provide in preserving and restoring functions of tissues compromised by irradiation. Included here are studies indicating that the cytokines interleukin 1, tumor necrosis factor, stem cell factor and interleukin 12 protect mice from radiation lethality when given prior to irradiation, and even in untreated mice these cytokines serve in innate defenses against external stimuli. In contrast, transforming growth factor beta, interleukin 6 and interferon, given before irradiation, sensitize the mice to radiation lethality. Myeloprotection against ionizing radiation and chemotherapeutic drugs by interleukin 1 depends on the regimen of treatment and may be related to the temporary patterns of induced cytokines and to the resulting changes in the cycling status of the progenitor cells. Interleukin 12, through induction and interaction with additional cytokines, has contrasting effects on different tissues, i.e., protecting the bone marrow but sensitizing the gut. Insights gained from such studies into the cellular mechanisms of regulation of radiation-induced damage by cytokines are discussed. Whether a "trade-off" of protection of some tissues and sensitization of other tissues applies to cytokine therapy in humans is unknown.

Animals↗
PubMed1997

Modulation with cytokines of radiation injury: suggested mechanisms of action.

Cytokines, hormonelike proteins, produced by stimulated cells and tissues, were found to protect mice against lethal hematopoietic failure caused by ionizing radiation. Radioprotection was achieved by pretreatment with interleukin-1 (IL-1), tumor necrosis factor (TNF), IL-12, or stem cell factor (SCF) at 18 to 24 hr before irradiation. Pretreatment with antibodies to these cytokines rendered the mice more susceptible to radiation lethality, indicating that these cytokines play a role in innate resistance to radiation. In contrast, treatment with tumor growth factor beta (TGF-beta), a cytokine that inhibits cycling of primitive hematopoietic progenitors, sensitized mice to radiation lethality. The schedule of IL-1 administration was critical to its radioprotective effect. Evidence was obtained that this may be based on the induction of additional cytokines by IL-1. The radioprotective effects of cytokines can be based on induction of cycling of primitive progenitor cells (IL-1, SCF), prevention of apoptosis (SCF), and induction of scavenging proteins and enzymes (IL-1, TNF) that reduce oxidative damage. In contrast, radiosensitizing effects may be due to inhibition of progenitor cycling (TGF-beta) or enhanced progenitor cell apoptosis (TGF-beta). Thus, the insights gained from such studies at the whole-animal level promise a better understanding of the membrane and intracellular events associated with radiation damage and repair of such damage.

Animals↗
PubMed1996

Cytokine-Induced Radiation Protection and Sensitization.

Cytokines, hormone-like proteins that are produced by stimulated cells and tissues, serve as intercellular messengers. The cloning and large-scale production in a recombinant form of an expanding number of cytokines in the past decade has permitted investigations aimed at assessing the benefit they may provide in preserving and restoring functions of tissues compromised by irradiation. This review focuses primarily on the preclinical and clinical findings of a number of radiation and chemotherapy studies in which cytokines were found to protect, restore, or at times harm the hematopoietic and gastrointestinal tissues, as well as lung and liver, against cytotoxic therapies. Included are the myelorestorative effects of cytokines, their application in mobilization of peripheral blood progenitor cells for bone marrow transplantation, and their myeloprotective effect when given before irradiation. Studies indicating the importance of the treatment schedule, and in some cases their contrasting effects on different tissues, are included. The insights gained from such studies into the mechanisms of regulation by cytokines of radiation-induced damage are discussed.

Journal Article↗
PubMed1996

Contrasting mechanisms of the myeloprotective effects of interleukin-1 against ionizing radiation and cytotoxic 5-fluorouracil.

Pretreatment with a single dose of interleukin-1 (IL-1) counteracts the myelosuppressive effects of radiation. In contrast, multiple doses are required to protect against several cytoablative drugs, suggesting different mechanisms. We examined the possibility that myeloprotection is due to IL-1-induced cycling of primitive progenitor cells. First, we evaluated the effect of the time between administration of IL-1 and 5-fluorouracil (5-FU), which kills cycling cells but spares quiescent early progenitors, on their interaction. Pretreatment with a single dose of IL-1 resulted in the death of mice treated with 5-FU provided IL-1 was given 18 h, but not 4 or 48 h, prior to administration of sublethal doses of 5-FU. Second, evaluation of primitive hematopoietic progenitor cells, 13-day spleen colony-forming units (CFU-S) and CFU with high proliferative potential revealed that treatment with 5-FU 18 h after administration of IL-1 results in reduction of CFU-S by 98% and of CFU with high proliferative potential by 65%, but only a 7 and 10% reduction, respectively, at 48 h. Third, in contrast to protection from death by pretreatment with a single dose of IL-1 at 24 h, two injections of IL-1 at 72 and 24 h before irradiation abrogated such protection. Similarly, the toxicity of 5-FU to progenitor cells was reduced when two injections of IL-1 were administered 48 h apart. This correlates with the time of up-regulation in the bone marrow cells of TGF-beta. These findings suggest that, depending on the schedule of treatment, administration of IL-1 may result in cycling of primitive progenitors, to protect against radiation, and may cause inhibition of cycling to protect against chemotherapeutic drugs.

Analysis of Variance↗
PubMed1995

Effect of liposome-mediated macrophage depletion on LPS-induced cytokine gene expression and radioprotection.

Tissue-specific cytokine mRNA expression was examined in mice that received LPS. In the liver, IL-6, IL-10, IL-12 (p40), and TNF-alpha were induced by 30 min after injection with LPS. In the spleen, IL-6 and TNF-alpha were induced by 30 min after LPS challenge, while increases in IL-10 and IL-12 (p40) were delayed in onset. GM-CSF, IFN-gamma, and IL-12 (p35) were not induced in the liver or spleen until 60 to 90 min after LPS injection. Mice were depleted of macrophages in their liver and spleen by i.v. injection of liposome-encapsulated dichloromethylene bisphosphonate (Cl2MBP). Induction of IL-1 beta, IL-6, IL-10, and IL-12 (p40) mRNA by LPS was reduced by > 95% in the liver of macrophage-depleted mice, implicating macrophages as the primary producers of these cytokines. Macrophage depletion resulted in a 50 to 75% reduction in TNF-alpha mRNA in the liver. The results from Cl2MBP-liposome-treated mice also suggested that splenic macrophages were the primary producers of LPS-induced IL-1 beta, IL-6, IL-12 (p40), and IL-1 receptor antagonist (IL-1ra) mRNA, but not IL-10 and TNF-alpha mRNA. Mice treated with Cl2MBP-liposomes were more susceptible to ionizing irradiation than control mice, whether or not they were administered a radioprotective dose of LPS. These findings suggest that depletion of liver and splenic macrophages results in a dysregulation of basal and LPS-induced cytokine responses that can be associated with an altered biologic response.

Animals↗
PubMed1995

In lethally irradiated mice interleukin-12 protects bone marrow but sensitizes intestinal tract to damage from ionizing radiation.

Administration of IL-12 prior to lethal irradiation, protected a significant fraction of mice from 60Co-gamma radiation-induced lethal hematopoietic syndrome. Radioprotection was associated with an increase in the number of c-kit+ bone marrow cells (BMC) in IL-12 treated mice compared to saline-treated mice. Even after supralethal doses of radiation (1200 cGy), IL-12-treated mice had twofold greater numbers of c-kit+ BMC than controls. However the mice receiving IL-12 and 1200 cGy died of the gastrointestinal (GI) syndrome, evident by gross necroscopy and histological evaluation, within 4 to 6 days after irradiation. Induction of the GI syndrome in mice not treated with IL-12 required radiation doses of 1600 cGy. Thus, at doses of radiation at which IL-12 still protects c-kit+ hematopoietic cells, it sensitizes the intestinal tract to damage. Radioprotection with IL-12 was abrogated by anti-IL-1R or anti-SCF antibody, but not anti-IFN gamma antibody. In contrast, anti-IFN gamma antibody abrogated sensitization of the intestinal tract by IL-12.

Animals↗
PubMed1995

Whole-body irradiation transiently diminishes the adrenocorticotropin response to recombinant human interleukin-1 alpha.

Recombinant human interleukin-1 alpha (rhIL-1 alpha) has significant potential as a radioprotector and/or treatment for radiation-induced hematopoietic injury. Both IL-1 and whole-body ionizing irradiation acutely stimulate the hypothalamic-pituitary-adrenal axis. We therefore assessed the interaction of whole-body irradiation and rhIL-1 alpha in altering the functioning of the axis in mice. Specifically, we determined the adrenocorticotropin (ACTH) and corticosterone responses to rhIL-1 alpha administered just before and hours to days after whole-body or sham irradiation. Our results indicate that whole-body irradiation does not potentiate the rhIL-1 alpha-induced increase in ACTH levels at the doses used. In fact, the rhIL-1 alpha-induced increase in plasma ACTH is transiently impaired when the cytokine is administered 5 h after, but not 1 h before, exposure to whole-body irradiation. The ACTH response may be inhibited by elevated corticosterone levels after whole-body irradiation, or by other radiation-induced effects on the pituitary gland and hypothalamus.

Adrenalectomy↗
PubMed1994

IL-12 protects bone marrow from and sensitizes intestinal tract to ionizing radiation.

IL-12, a potent stimulator of hemopoietic progenitor cells, was evaluated as a potential protector against 60Co-gamma radiation-induced lethal hemopoietic syndrome in mice. Administration of IL-12 before lethal irradiation of genetically distinct strains of mice, B6D2F1 and C3H/HeJ, protected a significant fraction of both strains of mice from death. Radioprotection was associated with a fivefold increase in the number of bone marrow cells at 6 days after irradiation. Even at supralethal doses of radiation (1200 cGy), the number of c-kit+ bone marrow cells 3 days after irradiation was twofold greater in IL-12-treated mice than in saline-treated mice. However, mice that received IL-12 and 1200 cGy (B6D2F1) or 900 cGy (C3H/HeJ) died of the gastrointestinal syndrome, as was evident by gross necroscopy and histologic evaluation, within 4 to 6 days after irradiation. Induction of the gastrointestinal syndrome in mice not treated with IL-12 required radiation doses of 1500 cGy or greater in both strains. Thus, at doses of radiation at which IL-12 still protects c-kit+ hemopoietic cells, it sensitizes the intestinal tract to damage. Radioprotection with IL-12 was abrogated by anti-IL-1R or anti-stem cell factor Ab. Anti-IFN-gamma Ab did not affect IL-12-induced hemopoietic radioprotection, but abrogated sensitization of the intestinal tract by IL-12. The sensitizing effect of IL-12 may be related to its ability to prime mice to subsequent inflammatory challenge, as demonstrated by an almost 100-fold increase in circulating TNF and IL-6 levels in normal B6D2F1 mice challenged with IL-12 and LPS. This priming effect of IL-12 also was abrogated by anti-IFN-gamma Ab.

Animals↗
PubMed1994

Decreased vasopressin content in parvocellular CRH neurosecretory system of Lewis rats.

Rats possess stress-responsive, vasopressin (VP)-expressing and stress-nonresponsive, VP-deficient subpopulations of parvocellular corticotropin-releasing hormone (CRH) neurosecretory cells. Both subpopulations are activated by bacterial lipopolysaccharide (LPS) and cytokines. Lewis rats exhibit hyporesponsive hypothalamo-pituitary-adrenocortical axes (HPAAs). The Lewis CRH neurosecretory system has been reported to be defective in females and normal in males. We used post-embedding electron microscopic (EM) immunocytochemistry to study baseline levels and LPS-stimulated depletion of neurosecretory vesicles. Male Lewis rats possessed normal numbers of CRH+/VP- varicosities and low numbers of CRH+/VP+ varicosities, indicating abnormally low release of VP into portal blood. This defect contrasts with the reported increase in VP content and release in magnocellular neurosecretory cells in Lewis rats.

Animals↗
PubMed1994

Synergy of IL-1 and stem cell factor in radioprotection of mice is associated with IL-1 up-regulation of mRNA and protein expression for c-kit on bone marrow cells.

Administration of IL-1 and stem cell factor (SCF) to mice 18 h before lethal 60Co whole-body irradiation resulted in synergistic radioprotection, as evidenced by increased numbers of mice surviving 1,200 to 1,300 cGy doses of radiation and the recovery of increased numbers of c-kit+ bone marrow cells at 1 and 4 days after the lethal dose of 950 cGy. Anti-SCF Ab inhibited IL-1-induced radioprotection, indicating that endogenous production of SCF is necessary for radioprotection by IL-1. Conversely, radioprotection induced by SCF was reduced by anti-IL-1R Ab, indicating that endogenous IL-1 contributes to SCF radioprotection. SCF, unlike IL-1 does not induce hemopoietic CSFs and IL-6 or gene expression of a scavenging mitochondrial enzyme manganese superoxide dismutase in the bone marrow, suggesting that SCF and IL-1 radioprotect by distinct pathways. The mRNA expression for c-kit (by Northern blot analysis) and 125I-SCF binding on bone marrow cells was elevated within 2 and 4 h of IL-1 administration respectively. Four days after LD 100/30 radiation the recovery of c-kit+ bone marrow cells was increased sixfold in IL-1-treated mice, almost 20-fold in SCF-treated mice, and 40-fold in mice treated with the combination of the two cytokines. Thus, endogenous production of both IL-1 and SCF is required for resistance to lethal irradiation and the synergistic radioprotective effect of the two cytokines may, in part, depend on IL-1 and SCF-induced increases in numbers of c-kit+ hemopoietic stem and progenitors cells that survive lethal irradiation.

Adrenalectomy↗
PubMed1994

Systemically administered histamine H1 and H2 receptor antagonists do not block the ACTH response to bacterial lipopolysaccharide and interleukin-1.

The administration of lipopolysaccharide (LPS) results in the activation of the hypothalamic-pituitary-adrenal axis (HPAA). We recently reported that the participation and interaction of LPS-induced proinflammatory cytokines were obligatory for the stimulation of adrenocorticotropic hormone (ACTH) release by LPS. LPS and LPS-derived cytokines also stimulate the release of histamine (HA). HA is a known hypothalamic neurotransmitter and activates the HPAA. Therefore, to elucidate the role of HA in LPS- and cytokine-induced ACTH release, we evaluated the effects of several HA H1 and H2 receptor antagonists on the ACTH response to LPS, recombinant human interleukin-1 alpha (rhIL-1 alpha) and HA in mice. Although all 3 of the H1 receptor antagonists administered (mepyramine (MEP), diphenhydramine (DPH) or promethazine (PMZ) were able to block the 10-min ACTH response to HA, only PMZ (a less selective H1 receptor antagonist than MEP) was able to reduce the LPS- or rhIL-1 alpha-induced ACTH responses. Ranitidine, a powerful and selective H2 receptor antagonist, had little effect on the LPS- and rhIL-1 alpha-induced ACTH responses, while metiamide (MET), a much less potent first-generation H2 receptor antagonist, substantially diminished ACTH release. The greater effectiveness of PMZ, in contrast to MEP or DPH, probably relates to the ability of phenothiazine derivatives to inhibit non-HA-dependent pathways involved in the stimulation of the HPAA by cytokines; the same may be true of MET.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1993

Antibodies chaperone circulating IL-6. Paradoxical effects of anti-IL-6 "neutralizing" antibodies in vivo.

In the baboon or the mouse, a stimulus such as LPS, TNF, or IL-1 typically led to a rapid induction of circulating IL-6, the levels peaked by 2 to 3 h and then declined to near-baseline values by 6 to 8 h. Administration to baboons or mice of "neutralizing" anti-IL-6 mAb followed by an IL-6 inducer led to a marked and sustained increase in circulating IL-6 levels. IL-6 Ag, IL-6 biologic activity, neutralizing anti-IL-6 mAb, and IL-6/anti-IL-6-mAb complexes could all be observed for an extended period of time (beyond 8 h) in the circulation of such animals. Nevertheless, in mice, if the anti-IL-6 mAb had been administered before the IL-6 inducer, there was a reduction in the in vivo IL-6-induced stimulation of fibrinogen levels, indicating that most of the intravascular IL-6 was not readily available for eliciting hepatocyte effects under these experimental conditions. Intraperitoneal administration into mice of mixtures of murine rIL-6 or human rIL-6 together with their respective anti-IL-6 mAb led to a marked increase in the appearance and longevity in the peripheral circulation of the exogenously administered murine or human rIL-6 species in a biologically active form. Varying the ratio of human rIL-6 to anti-human IL-6 mAb indicated that a molar ratio of 1:1 was sufficient for the ability of mAb to chaperone IL-6 in the murine circulation. Human rIL-6 mixed with "neutralizing" mAb in the approximate ratio 1:1 elicited an enhanced fibrinogen response in vivo in the mouse; an IL-6:mAb ratio of 1:125 led to a reduction in the fibrinogen response even though the levels of circulating B9 bioactivity and of human rIL-6-Ag were maximal under these conditions. Gel-filtration chromatographic and Western blotting analyses of IL-6 present in vivo in the mAb-free baboon revealed that although the IL-6 Ag was largely present in high molecular mass complexes of size 400 kDa in association with soluble IL-6 receptor, the B9 bioactivity was largely of low molecular mass (20 kDa). In contrast, in the anti-IL-6 mAb-treated baboon or mouse, the IL-6 Ag and bioactivity were both largely in complexes of 200 kDa. Thus, the binding of IL-6 in the intravascular compartment to other proteins, anti-IL-6 mAb in the present studies, gives IL-6 unexpected biochemical and pharmacologic properties in vivo.

Animals↗
PubMed1993

Inhibition of c-kit ligand/steel factor by antibodies reduces survival of lethally irradiated mice.

Survival after irradiation with LD100/30 (radiation dose lethal to 100% of mice in 30 days) is based on recovery of impaired hematopoietic function. Our previous studies using antibodies to interleukin-1 receptor (IL-1R), tumor necrosis factor (TNF), and IL-6 demonstrated that endogenous production of these three cytokines is required for untreated mice as well as mice protected with lipopolysaccharide (LPS), IL-1, or TNF to survive lethal irradiation. In this report we show that anti-c-kit ligand/steel factor (SIF) antibody similarly abrogates LPS- and IL-1-induced radioprotection. Furthermore, administration of this antibody to unmanipulated mice increased LD50/30 radiation lethality from 50% to 100%. Such an effect was not obtained using anti-IL-3, anti-IL-4, or anti-granulocyte-macrophage colony-stimulating factor antibody. Thus, like IL-1, TNF, and IL-6, SIF is required for survival from lethal irradiation.

Animals↗