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Biomedical subjects

A Cerami

Publications and source records attributed to A Cerami.

At least 145 records · Page 8Linked to original sources
PubMed1989

Myelopoietic enhancing effects of murine macrophage inflammatory proteins 1 and 2 on colony formation in vitro by murine and human bone marrow granulocyte/macrophage progenitor cells.

Two recently identified and purified murine macrophage inflammatory proteins MIP-1 and MIP-2 were tested in vitro both alone, and in combination with purified recombinant (r) murine (mu) GM-CSF, natural (n)muCSF-1, or rhuman (hu)G-CSF, for effects on mouse marrow CFU-GM, in combination with erythropoietin for effects on mouse marrow BFU-E, and in combination with rhuGM-CSF or rhuG-CSF for effects on human marrow CFU-GM. MIP-1 and MIP-2 did not stimulate, but did enhance by up to threefold, colony formation of mouse CFU-GM co-stimulated by rmuGM-CSF and nmuCSF-1, but not by rhuG-CSF, in the absence or presence of serum. MIP-1 and MIP-2 were maximally active at concentrations greater than or equal to 100 ng/ml and the actions appeared to be initiated during the DNA synthetic portion of the cell cycle. Neither MIP-1 nor MIP-2 at up to 1 microgram/ml had any effect on mouse BFU-E, in the absence or presence of erythropoietin. Both MIP-1 and MIP-2 had direct acting effects on purified mouse CFU-GM. The cloning efficiency of 200 purified cells plated with 50 U muCSF-1 was 82% with and 43% without MIP; the cloning efficiency with 50 U rmuGM-CSF was 65% with and 35% without MIP. MIP effects were not mimicked by bacterial LPS, rhuIL-1 alpha, rhuIL-6, or rmuIL-4, and were neutralized by their respective specific antibodies. MIP-1 and MIP-2 also enhanced endogenously stimulated and rhuGM-CSF-, but not rhuG-CSF-, stimulated colony formation by human marrow CFU-GM. These results demonstrate a new role for MIP-1 and MIP-2 in vitro as myelopoietic enhancing activities for CFU-GM.

Animals↗
PubMed1989

Macrophage inflammatory protein-1: a prostaglandin-independent endogenous pyrogen.

Macrophage inflammatory protein-1 (MIP-1) produced a monophasic fever of rapid onset whose magnitude was equal to or greater than that of fevers produced with either recombinant human cachectin (or tumor necrosis factor) or recombinant human interleukin-1. However, in contrast to these two endogenous pyrogens, the fever induced by MIP-1 was not inhibited by the cyclooxygenase inhibitor ibuprofen. Thus, MIP-1 may participate in the febrile response that is not mediated through prostaglandin synthesis and clinically cannot be ablated by cyclooxygenase inhibitors.

Animals↗
PubMed1989

Infection and labor. IV. Cachectin-tumor necrosis factor in the amniotic fluid of women with intraamniotic infection and preterm labor.

A growing body of evidence supports a causal link between subclinical intrauterine infection and preterm labor. The mechanisms responsible for the onset of parturition in this setting have not been elucidated. The conventional view has been that bacterial products increase prostaglandin biosynthesis by intrauterine tissues and this, in turn, leads to the onset of labor. An alternative or complementary mechanism is that microbial products activate the host monocyte-macrophage system and that cytokines released during this process signal the initiation of parturition by stimulating prostaglandin biosynthesis by intrauterine tissues. This study was conducted to determine if cachectin-tumor necrosis factor is present in the amniotic fluid of women with intraamniotic infection and whether this cytokine can alter the rate of prostaglandin biosynthesis by intrauterine tissues. Amniotic fluid from 54 women was assayed for tumor necrosis factor. Tumor necrosis factor was not detectable in the amniotic fluid of women without intraamniotic infection regardless of the presence or absence of term or preterm labor. On the other hand, the amniotic fluid of 11 of 15 women with preterm labor and intraamniotic infection had measurable tumor necrosis factor. This cytokine stimulated prostaglandin E2 biosynthesis by amnion cells in monolayer culture in a dose-dependent fashion. These data support the concept that macrophage activation is involved in the onset of human parturition in the setting of infection. We propose that the host (fetus and/or mother) signals the onset of parturition through the secretion of inflammatory cytokines released in response to bacterial invasion.

Amnion↗
PubMed1989

Cachectin/tumor necrosis factor and other cytokines in infectious disease.

The studies reviewed here represent but a fraction of those published in the field last year, but they serve to illustrate two important points: (1) the cytokine network possesses enormous diversity of biological function, and (2) it is redundant, such that overlapping and synergistic effects are observed between many different cytokines. The impact of this system on the host is pervasive and readily amplifiable, and integrates the diverse responses to infectious disease which may be either beneficial, protecting against infection, or deleterious, causing tissue injury and death. The example of cachectin/TNF illustrates this type of scenario: during local infection or inflammation, low levels of cachectin/TNF act to enhance immune responsiveness, stimulate blood-vessel growth, increase energy mobilization, induce the release of other cytokines, and promote wound-healing; when overwhelming infection occurs, as in septicemia, large quantities of cachectin/TNF reach the circulation and cause shock, MSOF, and death; if a persisting infection develops and cachectin/TNF is chronically secreted, it mediates a state of cachexia which may be fatal. Future studies will undoubtedly advance our understanding of these effects, and that of the other cytokines. The development of novel therapies for inflammation, septic shock, and cachexia may be based on such advances.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Cachectin/tumor necrosis factor production by fetal and newborn rat hepatic macrophages.

The capacity of fetal and newborn hepatic macrophages to produce cachectin/tumor necrosis factor (TNF) has not been previously examined. The role that TNF plays in newborn infection is also unknown. In the present report, fetal and newborn rat hepatic macrophages have been maintained in short-term tissue culture, and are shown to produce TNF in response to in-vitro endotoxin stimulation. Cells obtained are morphologically and antigenically consistent with macrophages, and are depleted of accessory cells and lymphocytes. In response to increasing doses of endotoxin, fetal and newborn hepatic macrophages produce TNF, and this production is suppressed fully by pretreatment with dexamethasone. The results demonstrate that fetal and newborn hepatic macrophages possess the capability to produce TNF in vitro. We propose that TNF may play a role in the response of the fetus and newborn to bacterial infection.

Animals↗
PubMed1989

Identification and characterization of macrophage inflammatory protein 2.

In response to endotoxin, macrophages secrete a protein with a molecular mass of approximately 6000 Da and with an affinity for heparin. This protein, which we term "macrophage inflammatory protein 2," is a potent chemotactic agent for human polymorphonuclear leukocytes. In addition, subcutaneous administration of the monokine causes a localized inflammatory reaction. Partial N-terminal sequence data reveal similarity to a family of proteins, the archetype of which is platelet factor 4. Although macrophage inflammatory protein 2 is a distinct member of the platelet factor 4 family, its sequence is most closely related to that of the gro/KC gene product, which is expressed in transformed or platelet-derived growth factor-treated cells.

Amino Acid Sequence↗
PubMed1989

Trypanothione is the primary target for arsenical drugs against African trypanosomes.

The trypanosomatid metabolite N1,N8-bis-(glutathionyl)spermidine (trypanothione) has been demonstrated to form a stable adduct with the aromatic arsenical drug melarsen oxide [p-(4,6-diamino-s-triazinyl-2-yl)aminophenyl arsenoxide]. The stability constant of the melarsen-trypanothione adduct (Mel T) has been determined to be 1.05 x 10(7) M-1. When bloodstream Trypanosoma brucei are incubated with either melarsen oxide or the 2,3-dimercaptopropanol adduct of melarsen oxide (melarsoprol), Mel T is the only arsenical derivative detectable in acid-soluble extracts of the cells. Trypanothione may therefore be regarded as a primary target for aromatic arsenical derivatives against African trypanosomes. The selective toxic action of these compounds might arise through sequestration of intracellular trypanothione in the form of Mel T, or Mel T itself may be toxic within the cell. The latter possibility is illustrated by the finding that Mel T is an inhibitor of trypanothione reductase from T. brucei (Ki = 9.0 microM)--an enzyme that is central to the regulation of the thiol/disulfide redox balance in the parasite and absent from the host.

Animals↗
PubMed1989

Macrophage inflammatory proteins 1 and 2: members of a novel superfamily of cytokines.

A number of studies of inflammation and of cell growth and transformation have recently converged by defining two related families of cytokines. The first, represented by macrophage inflammatory protein 1, is composed of several gene products that have been identified in activated T cells, macrophages, and fibroblasts. The biological activities of this family are still being characterized but so far include effects on neutrophils, monocytes, and hematopoietic cells. The second, represented by macrophage inflammatory protein 2, includes platelet products such as platelet factor 4 and beta-thromboglobulin as well as several other recently described gene products that have effects on a number of cell types including neutrophils, fibroblasts, hematopoietic cells, and melanoma cells. The two families are structurally related and may have evolved from a common ancestral gene that duplicated and then diverged. Their differential control and expression in a wide variety of cell types suggests that they may have multiple functions in regulating inflammation and cell growth.

Amino Acid Sequence↗
PubMed1989

Cachectin/tumor necrosis factor-alpha alters red blood cell kinetics and induces anemia in vivo.

Chronic inflammatory diseases are often associated with decreased red blood cell (RBC) mass. The cytokines cachectin/tumor necrosis factor-alpha (TNF) and interleukin 1 (IL 1) are produced by monocytes/macrophages in response to many inflammatory stimuli and have been implicated in the anemia of chronic disease. This study was undertaken to evaluate the mechanisms by which cachectin/TNF, IL 1, or endotoxin induce anemia. Hematologic parameters and RBC kinetics were quantitated in rats given chronic sublethal quantities of either recombinant human cachectin/TNF, recombinant human IL 1 alpha, or Salmonella endotoxin for 7 days. Cachectin/TNF or endotoxin treatment resulted in a 25 or 31% decrease, respectively, in total RBC mass, whereas RBC mass was unchanged by IL 1 administration. Anemia associated with either chronic cachectin or endotoxin administration was characterized by normal mean corpuscular volume, mean corpuscular hemoglobin content, and reticulocyte numbers. [59Fe]RBC survival was significantly shortened in animals given cachectin, IL 1 or endotoxin, but the magnitude of the response was greatest in cachectin/TNF-or endotoxin-treated rats. Although cachectin/TNF-IL 1-, or endotoxin treatment resulted in similar hypoferremia and shortened plasma iron half-life, endotoxin or cachectin/TNF treatment (but not IL 1) significantly reduced the incorporation of plasma 59Fe into newly synthesized RBCs. We conclude that chronic cachectin/TNF administration produces anemia by decreasing RBC synthesis and reducing the life span of circulating RBCs. An endogenous cachectin/TNF response during inflammatory disease may contribute to an associated anemic state, whereas the modestly reduced red cell life span induced by IL 1 does not lead to a net reduction in RBC mass, presumably owing to a preserved RBC synthetic rate.

Anemia↗
PubMed1989

Anticachectin/tumor necrosis factor-alpha antibodies attenuate development of cachexia in tumor models.

C57BL/6 mice bearing either a transplantable methylcholanthrene-induced sarcoma or Lewis lung adenocarcinoma were passively immunized every other day with a rabbit immunoglobulin fraction raised against murine cachectin/tumor necrosis factor-alpha. Mice bearing methylcholanthrene-induced sarcoma developed tumor-associated hypophagia that was attenuated by anticachectin immunoglobulin treatment. In the same tumor-bearing animals, anticachectin treatment also significantly reduced the extent of carcass protein and fat loss, and reduced tumor weight. Mice bearing Lewis lung adenocarcinoma did not develop significant anorexia or carcass lean tissue depletion as tumor growth progressed, but they lost carcass lipid. Treatment of Lewis lung adenocarcinoma bearing mice with anticachectin antibodies diminished the degree of carcass lipid depletion and prevented plasma hypertriglyceridemia. However, in both tumor models, anticachectin treatment did not affect either the development of anemia, hypoalbuminemia or the increase in serum amyloid P concentrations seen with increasing tumor burden. We conclude that an endogenous cachectin response, inhibitable by exogenously administered antibody, contributes to anorexia and to changes in body fat and protein metabolism in these tumor-bearing animals. Neutralizing endogenous cachectin production with antibodies offers the potential to reduce tissue wasting that is frequently associated with neoplastic disease, but it does not appear to affect all of the hematologic and acute phase responses in these murine tumor models.

Adenocarcinoma↗
PubMed1989

Studies of cachexia in parasitic infection.

Cachexia and septic shock, syndromes associated with chronic and acute infection, respectively, are mediated by endogenous factors. The search for humoral mediators of cachexia led to the isolation of the cytokine known as cachectin/TNF. A biologic role for cachectin/TNF in cachexia has been identified: it induces a catabolic state in adipose and skeletal muscle cells in vitro, and animals persistently exposed to it in vivo become cachectic. Cachectin/TNF was also discovered to be a primary, essential mediator of septic shock. The acute administration of the recombinant protein causes shock, tissue injury, and derangements of metabolic homeostasis that mimic endotoxemia and septic shock syndrome. Anti-cachectin antibodies protect against the lethal effects of septic shock and cachexia, suggesting that this mediator has a central role as a trigger to the inflammatory and deleterious host responses to infection. Future investigations will undoubtedly be directed towards the effects of inhibiting cachectin/TNF in the treatment of the complications of infectious disease.

Animals↗
PubMed1989

Cachectin/TNF or IL-1 alpha induces cachexia with redistribution of body proteins.

Macrophage secretory products are suspected to participate in the severe lean tissue wasting related to chronic illness. The protein metabolic effects of chronic, 7-day cachectin/tumor necrosis factor (cachectin) or interleukin 1 alpha (IL-1 alpha) administration in vivo were studied in male Wistar rats that were 1) freely fed, 2) pair fed, 3) total protein and calorie starved, 4) twice daily lipopolysaccharide (LPS) administered, 5) twice daily cachectin administered, and 6) twice daily IL-1 alpha administered. LPS, cachectin, or IL-1 alpha administration produced anorexia; weight loss in these groups was comparable to respective pair-fed animals. However, LPS, cachectin, or IL-1 alpha accelerated peripheral protein wasting while preserving liver protein content, unlike the pattern in the pair-fed or starved animals in which loss of liver proteins and relative preservation of skeletal muscle protein were observed. The decrease in skeletal muscle protein content in LPS- or cytokine-treated animals was associated with coordinate decreases in muscle mRNA levels for the myofibrillar proteins myosin heavy chain, myosin light chain, actin, and in the 18S and 28S subunits of ribosomal RNA. We conclude that chronic exposure to the cytokines, IL-1 alpha or cachectin, can simulate those body and muscle protein changes seen in experimental LPS administration or chronic disease and markedly differ from the pattern of protein redistribution due to caloric restriction.

Animals↗
PubMed1989

Macrophage receptor-mediated processing and regulation of advanced glycosylation endproduct (AGE)-modified proteins: role in diabetes and aging.

Tissue and cell surface proteins modified nonenzymatically by glucose are shown to be removed by macrophages through a recently characterized high affinity receptor. Insulin appears to be a potent suppressor of this macrophage AGE removal activity, while TNF acts as a stimulant. Coupling of AGE-proteins to their AGE-receptor results in TNF and IL-1 synthesis and secretion. This suggests that AGE may act as a signal for growth-promoting factor secretion in a coordinated replacement process during tissue remodeling. A greater than 2-fold decrease in receptor number and binding capacity found in cells from aged mice as compared to young suggests that aging may adversely affect the AGE-receptor-efficiency and by impeding crosslinked AGE-protein removal add to ongoing aging tissue damage.

Aging↗