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R Neta

Publications and source records attributed to R Neta.

At least 55 records · Page 3Linked to original sources
PubMed1990

Radioprotection of mice with interleukin-1: relationship to the number of erythroid and granulocyte-macrophage colony-forming cells.

This report presents the results of an investigation of changes in the number of erythroid and granulocyte-macrophage colony-forming cells (GM-CFC) that had occurred in tissues of normal B6D2F1 mice 20 h after administration of a radioprotective dose (150 ng) of human recombinant interleukin-1 (rIL-1). Neutrophilia in the peripheral blood and changes in the tissue distribution of GM-CFC demonstrated that cells were mobilized from the bone marrow in response to rIL-1 injection. For example, 20 h after rIL-1 injection marrow GM-CFC numbers were 80% of the numbers in bone marrow from saline-injected mice. Associated with this decrease there was a twofold increase in the number of peripheral blood and splenic GM-CFC. Also, as determined by hydroxyurea injection, there was an increase in the number of GM-CFC in S phase of the cell cycle in the spleen, but not in the bone marrow. Data in this report suggest that when compared to the spleen, stimulation of granulopoiesis after rIL-1 injection is delayed in the bone marrow. Also, the earlier recovery of GM-CFC in the bone marrow of irradiated mice is not dependent upon an increase in the number of GM-CFC at the time of irradiation.

Animals↗
PubMed1989

Interleukin-1 enhances survival of lethally irradiated mice treated with allogeneic bone marrow cells.

Interleukin-1 (IL-1) enhanced the capacity of allogeneic bone marrow (BM) cells to promote survival of mice given doses of radiation (1,200 to 1,350 cGy) that are significantly higher than those generally used for BM ablation (850 to 950 cGy). Three to five times greater numbers of lethally irradiated (1,200 to 1,350 cGy) C57B1/6 (H-2b) mice given 10(7) T-cell-depleted Balb/c (H-2d) BM cells survived over 6 weeks if also treated with a single intraperitoneal (IP) dose of 10 micrograms IL-1 20 hours before or from 1 to 3 hours after radiation. The spleens of these mice were reconstituted predominantly, but not exclusively, with donor cells (54% to 91%). Histologic examination of the epidermal and gastrointestinal tissues of mice surviving more than 6 weeks did not reveal any evidence of graft-versus-host (GVH) disease; however, since 10% to 43% of the mice died between days 30 and 46, the possibility of a GVH syndrome in these mice cannot be excluded. The spleen cells from irradiated mice given BM transplants and IL-1, which consisted of greater than or equal to 85% donor cells, were able to generate specific T-cell cytotoxic killing of unrelated allogeneic donor cells but were unreactive to target cells bearing either host or donor major histocompatibility complex (MHC) class I antigens. Thus, long-term mixed chimeric survivors were tolerant to recipient and donor alloantigens but exhibited immunologic competence. These results show that IL-1 promotes survival of lethally irradiated mice and that allogeneic hematopoietic cells in such animals develop tolerance to host MHC antigens. Although there are many unanswered questions, these data suggest that IL-1 may prove clinically useful in promoting BM engraftment.

Animals↗
PubMed1989

Radioprotection of mice with interleukin-1: relationship to the number of spleen colony-forming units.

Compared to saline-injected mice 9 days after 6.5 Gy irradiation, there were twofold more Day 8 spleen colony-forming units (CFU-S) per femur and per spleen from B6D2F1 mice administered a radioprotective dose of human recombinant interleukin-1-alpha (rIL-1) 20 h prior to their irradiation. Studies in the present report compared the numbers of CFU-S in nonirradiated mice 20 h after saline or rIL-1 injection. Prior to irradiation, the number of Day 8 CFU-S was not significantly different in the bone marrow or spleens from saline-injected mice and rIL-1-injected mice. Also, in the bone marrow, the number of Day 12 CFU-S was similar for both groups of mice. Similar seeding efficiencies for CFU-S and percentage of CFU-S in S phase of the cell cycle provided further evidence that rIL-1 injection did not increase the number of CFU-S prior to irradiation. In a marrow repopulation assay, cellularity as well as the number of erythroid colony-forming units, erythroid burst-forming units, and granulocyte-macrophage colony-forming cells per femur of lethally irradiated mice were not increased in recipient mice of donor cells from rIL-1-injected mice. These results demonstrated that a twofold increase in the number of CFU-S at the time of irradiation was not necessary for the earlier recovery of CFU-S observed in mice irradiated with sublethal doses of radiation 20 h after rIL-1 injection.

Animals↗
PubMed1988

Interaction of recombinant IL-1 and recombinant tumor necrosis factor in the induction of mouse acute phase proteins.

Recombinant mouse and human IL-1 (alpha and beta forms), as well as rTNF-alpha when administered in vivo, induced the production of the mouse acute phase reactants: serum amyloid P-component (SAP), C3, and fibrinogen. The SAP response to all three rIL-1 proteins reached a maximum at a dose of 10(4) U/mouse, which corresponds to 1 to 10 micrograms of protein. The maximum in vivo response consisted of a 10-fold increase in SAP levels, a 2-fold increase in C3 levels, and a 3-fold increase in fibrinogen concentration. By contrast, rTNF-alpha induced a much smaller acute phase (AP) protein response (4-fold increase in SAP) when administered in vivo. Administration of a combination if rIL-1 and rTNF resulted in an AP response that was additive for SAP, synergistic for fibrinogen, but resulted in only the same amount of C3 induced by IL-1 alone. Both recombinant monokines induced new SAP synthesis by isolated hepatocytes in vitro with an optimal response occurring with either 1 U of rIL-1/ml per 2 x 10(5) hepatocytes or 10(-3) U/ml of rTNF. The hepatocyte response to IL-1 was of the same magnitude as the response of intact mice; however, the response to TNF was approximately 10(4) times more efficient in vitro. A mixture of the monokines induced an in vitro SAP response that was additive when suboptimal doses of rIL-1 were combined with optimal amounts of rTNF-alpha. Overall, the findings indicate that both monokines directly trigger hepatocyte synthesis of SAP and that their combined effect probably accounts for a substantial portion of the synthesis of these AP proteins in mice.

Acute-Phase Proteins↗
PubMed1988

Interdependence of the radioprotective effects of human recombinant interleukin 1 alpha, tumor necrosis factor alpha, granulocyte colony-stimulating factor, and murine recombinant granulocyte-macrophage colony-stimulating factor.

Interleukin 1 alpha (IL-1 alpha), tumor necrosis factor alpha (TNF alpha), granulocyte-colony-stimulating factor (G-CSF), and granulocyte-macrophage colony-stimulating factor (GM-CSF) are molecularly distinct cytokines acting on separate receptors. The release of these cytokines can be concomitantly induced by the same signal and from the same cellular source, suggesting that they may cooperate. Administered alone, human recombinant (hr)IL-1 alpha and hrTNF alpha protect lethally irradiated mice from death, whereas murine recombinant GM-CSF and hrG-CSF do not confer similar protection. On a dose basis, IL-1 alpha is a more efficient radioprotector than TNF alpha. At optimal doses, IL-1 alpha is a more radioprotective cytokine than TNF alpha in C57BL/6 and B6D2F1 mice and less effective than TNF alpha in C3H/HeN mice, suggesting that the relative effectiveness of TNF alpha and IL-1 alpha depends on the genetic makeup of the host. Administration of the two cytokines in combination results in additive radioprotection in all three strains. This suggests that the two cytokines act through different radioprotective pathways and argues against their apparent redundancy. Suboptimal, nonradioprotective doses of IL-1 alpha also synergize with GM-CSF or G-CSF to confer optimal radioprotection, suggesting that such an interaction may be necessary for radioprotection of hemopoietic progenitor cells.

Animals↗
PubMed1988

Recombinant interleukin-1 alpha and recombinant tumor necrosis factor alpha synergize in vivo to induce early endotoxin tolerance and associated hematopoietic changes.

Endotoxin, the lipopolysaccharide (LPS) derived from gram-negative bacteria, invokes a wide range of responses in susceptible hosts. It is known that virtually all responses to LPS are mediated by the action of macrophage-derived cytokines (such as interleukin-1 [IL-1], tumor necrosis factor [TNF], and others) which are produced principally by macrophages and maximally within several hours of LPS administration. One manifestation of LPS administration which is not well understood is the phenomenon of "early endotoxin tolerance." In response to a single sublethal injection of LPS, experimental animals become refractory to challenge with a homologous or heterologous LPS preparation 3 to 4 days later. Animals rendered tolerant exhibit mitigated toxicity and a reduced capacity to produce circulating cytokines (i.e., colony-stimulating factor or interferon) in response to the challenge LPS injection. Previous studies have also shown that this state of transient, acquired hyporesponsiveness to LPS is accompanied by a marked increase in the size of cells in the bone marrow which are enriched in numbers of macrophage progenitors. In this study, we examined the capacity of recombinant IL-1 or recombinant TNF or both to induce early endotoxin tolerance and its associated hematopoietic changes. Neither cytokine alone was able to mimic LPS for induction of tolerance. Combined administration of recombinant IL-1 and recombinant TNF doses which were not toxic when administered individually led to synergistic toxicity (as assessed by death or weight loss). However, within a nontoxic range, the two cytokines synergized to induce a significant reduction in the capacity to produce colony-stimulating factor in response to LPS, as well as the characteristic increase in bone marrow cell size and macrophage progenitors shown previously to be associated with LPS-induced tolerance.

Animals↗
PubMed1988

Cytokines in therapy of radiation injury.

Repeated injections or infusion of hematopoietic growth factors, such as interleukin-3 (IL-3), granulocyte macrophage-colony stimulating factor (GM-CSF), or granulocyte-colony stimulating factor (G-CSF), accelerate restoration of hematopoiesis in animals compromised by sublethal doses of cytotoxic drugs or irradiation. Previous work by the investigators has shown that IL-1 induced circulating CSF in normal mice and, when used after sublethal irradiation, accelerated the recovery of endogenous splenic colonies. Therefore, IL-1, as well as IFN-gamma, tumor necrosis factor (TNF), G-CSF, and GM-CSF, were evaluated as potential therapeutic agents in irradiated C3H-HeN mice. A single intraperitoneal injection, administered within three hours after a lethal dose (LD)95/30 of irradiation that would kill 95% of mice within 30 days, protected in a dose-dependent manner up to 100% of mice from radiation-induced death due to hematopoietic syndrome. Significant therapeutic effects were also achieved with a single dose of IFN-gamma or of TNF. In contrast, GM-CSF and G-CSF, administered shortly after irradiation, had no effect in the doses used on mice survival.

Animals↗
PubMed1988

Aspects of cytokine induced modulation of immunity and inflammation with emphasis on interleukin 1.

Interleukin 1 (IL 1) contributes to both acute and chronic inflammatory processes. Purified IL 1 by itself is only one of the signals that induces local inflammation. The contribution of IL 1 to local inflammatory reactions is influenced by exogenous stimuli, antagonists such as steroid hormones and TGF beta (tissue growth factor beta) and agonists such as TNF (tissue necrosis factor). IL 1 production is depressed by glucocorticoids, but glucocorticoids induce expression of receptors for IL 1 on selected cell types including B lymphocytes and fibroblasts. Thus, complex interactions between hormones and cytokines modulate immunological and inflammatory responses.

Animals↗
PubMed1988

Comparison of in vivo effects of human recombinant IL 1 and human recombinant IL 6 in mice.

IL 1 and IL 6 share a number of biological activities, including induction of fever, neutrophilia and acute phase response, and IL 1 induces IL 6 production by fibroblasts and macrophages. Therefore, it was proposed that IL 6 mediates many of the activities of IL 1. To test this hypothesis in vivo, we assessed induction of IL 6 following IL 1 alpha administration to mice and tested IL 6 for radioprotection and induction of early (CSF) and late (fibrinogen and SAA) acute phase reactants. IL 1 alpha given to mice ip induced, in a dose dependent manner, detectable IL 6 in circulation, with maximal titers at 2-4 hrs. However, unlike IL 1 which is 10-1000 ng/mouse of human recombinant IL 6 did not result in increased survival of mice following lethal irradiation. In fact, such treatment given 20 hrs before LD50/30 doses of radiation resulted in reduced survival of mice. However, IL 6 augmented the radioprotective effect of IL 1. IL 1 in doses above 10 ng/mouse induced within 2 to 6 hrs a dose dependent increase in CSF in circulation, but IL 6 did not induce detectable levels of CSF at 2, 6 and 20 hrs after administration. Administration of IL 6 to mice produced a dose dependent increase in circulating fibrinogen and SAA. Similarly, administration of IL 1 resulted in much greater increases in levels of fibrinogen and SAA. Therefore, IL 1 is a more effective inducer of fibrinogen and SAA in mice than is IL 6. Although definitive conclusions concerning the relative roles for IL 1 and IL 6 in vivo will await availability of anti IL 1 and anti-IL 6 antibodies, our data do not support the suggestion that the above IL 1 effects can be attributed solely to IL 6.

Acute-Phase Reaction↗
PubMed1988

Recovery of hematopoietic colony-forming cells in irradiated mice pretreated with interleukin 1 (IL-1).

Data in this report determined the effect of a single injection of recombinant interleukin 1 alpha (rIL-1) prior to irradiation of B6D2F1 mice on the recovery of colony-forming cells (CFC) at early and late times after sublethal and lethal doses of radiation. Injection of rIL-1 promoted an earlier recovery of mature cells in the blood and CFC in the bone marrow and spleen. For example, 8 days after 6.5 Gy irradiation, the number of CFU-E (colony-forming units-erythroid), BFU-E (burst-forming units-erythroid), and GM-CFC (granulocyte-macrophage colony-forming cells) per femur was approximately 1.5-fold higher in rIL-1-injected mice than in saline-injected mice. Also, 5, 9, and 12 days after irradiation, the number of both day 8 and day 12 CFU-S (colony-forming units-spleen) was almost twofold greater in bone marrow from rIL-1-injected mice. The earlier recovery of CFU-S in rIL-1-injected mice was not associated with an increase in the number of CFU-S that survived immediately after irradiation. Also, 7 months after irradiation, the number of CFU-S per femur of both saline- and rIL-1-injected mice was still less than 50% of normal values. Data in this report demonstrate that a single injection of rIL-1 prior to irradiation accelerates early hematopoietic recovery in irradiated mice, but does not prevent expression of radiation-induced frontend damage or long-term damage to hematopoietic tissues.

Animals↗
PubMed1987

The in vivo effects of interleukin 1. I. Bone marrow cells are induced to cycle after administration of interleukin 1.

We have previously reported that interleukin 1 (IL-1) administration 20 hr before irradiation protects mice from lethal effects of radiation. The recovery of total nucleated bone marrow cells and of hematopoietic progenitor cells was enhanced in IL-1 treated, as compared to untreated, irradiated mice. This suggested that IL-1 administration may affect the cells in the bone marrow of normal mice. Intraperitoneal administration of recombinant IL-1 resulted in bone marrow cell enlargement and increased cycling of these enlarged cells. In addition, the capacity of bone marrow cells from IL-1 treated mice to proliferate in response to granulocyte macrophage-colony-stimulating factor (GM-CSF) in cell suspension cultures was enhanced. The above effects were not genetically restricted as C57BL/6, B6D2F1, C3H/HeN, and C3H/HeJ mice showed similar responses. A comparative study showed that 100 ng of IL-1 was much more effective in stimulating bone marrow cells by the above criteria than 5 micrograms GM-CSF. Since IL-1, unlike CSF, can not be demonstrated to have a direct in vitro stimulatory effect on bone marrow cells, the aforementioned in vivo effects of IL-1 are presumably mediated by other hematopoietic growth factors. We have previously shown that IL-1 induces the appearance of high titers of CSF in the serum. Consequently hematopoietic growth factors that are generated at local sites following IL-1 administration may mediate the observed cell cycling effect.

Animals↗
PubMed1987

Induction of colony stimulating factor in vivo by recombinant interleukin 1 alpha and recombinant tumor necrosis factor alpha 1.

In response to a potent inflammatory challenge, such as Gram-negative endotoxin, a number of cytokines are induced that, in turn, mediate many of the pathophysiologic alterations associated with endotoxicity. In this study, we have observed two endotoxin-associated monokines, recombinant interleukin-1 alpha (rIL 1 alpha) and recombinant tumor necrosis factor alpha (rTNF alpha), to induce colony stimulating factor (CSF) in vivo. The CSF activities produced in response to rIL 1 alpha or rTNF alpha gave rise to a mixture of granulocyte-macrophage colonies and were induced in a dose- and time-dependent fashion, peaking within 3 hr of cytokine injection (preceding peak CSF induction by endotoxin by several hours). Combined injection of suboptimal concentrations of rIL 1 alpha and rTNF alpha were additive, and simultaneous injection of optimal concentrations of each failed to increase CSF levels over that observed with either cytokine alone. Unlike endotoxin, neither cytokine induced interferon in vivo. These findings extend our understanding of the cytokine cascade that is operative in an inflammatory response and may account for many of the observed hematopoietic alterations that accompany inflammation.

Animals↗