Biomedical subjects

G Fantuzzi

Publications and source records attributed to G Fantuzzi.

At least 37 records · Page 2Linked to original sources

PubMed2000

Structural requirements of six naturally occurring isoforms of the IL-18 binding protein to inhibit IL-18.

A novel, constitutively expressed and secreted IL-18 binding protein (IL-18BP) neutralizes IL-18 and thereby suppresses the production of IFN-gamma, resulting in reduced T-helper type 1 immune responses. In the present study, four human and two mouse isoforms, resulting from mRNA splicing and found in various cDNA libraries, were expressed, purified, and assessed for binding and neutralization of IL-18 biological activities. Human IL-18BP isoform a (IL-18BPa) exhibited the greatest affinity for IL-18 with a rapid on-rate, a slow off-rate, and a dissociation constant (K(d)) of 399 pM. IL-18BPc shares the Ig domain of IL-18BPa except for the 29 C-terminal amino acids; the K(d) of IL-18BPc is 10-fold less (2.94 nM). Nevertheless, IL-18BPa and IL-18BPc neutralize IL-18 >95% at a molar excess of two. IL-18BPb and IL-18BPd isoforms lack a complete Ig domain and lack the ability to bind or neutralize IL-18. Murine IL-18BPc and IL-18BPd isoforms, possessing the identical Ig domain, also neutralize >95% murine IL-18 at a molar excess of two. However, murine IL-18BPd, which shares a common C-terminal motif with human IL-18BPa, also neutralizes human IL-18. Molecular modeling identified a large mixed electrostatic and hydrophobic binding site in the Ig domain of IL-18BP, which could account for its high affinity binding to the ligand. It is likely that preferential secretion of functional and nonfunctional isoforms of IL-18BP affect the immune response.

Amino Acid Sequence↗

PubMed2000

IL-18 regulates IL-1beta-dependent hepatic melanoma metastasis via vascular cell adhesion molecule-1.

Proinflammatory cytokines, including IL-1beta and tumor necrosis factor-alpha (TNF-alpha), promote cancer cell adhesion and liver metastases by up-regulating the expression of vascular cell adhesion molecule-1 (VCAM-1) on hepatic sinusoidal endothelium (HSE). In this study, hepatic metastasis after intrasplenically injected mouse B16 melanoma (B16M) cells was reduced 84-95% in mice with null mutations for either IL-1beta or the IL-1beta-converting enzyme (ICE, caspase-1) compared with wild-type mice. On day 12, 47% of wild-type mice were dead compared with 19% of either IL-1beta or ICE-deficient mice. In vitro, conditioned medium from B16M cells (B16M-CM) induced the release of TNF-alpha and IL-1beta from cultures of primary murine HSE. The effect of B16M-CM on HSE resulted in increased numbers of B16M cells adhering to HSE, which was completely abrogated by a specific inhibitor of ICE, anti-IL-18 or IL-18-binding protein. Exogenous IL-18 added to HSE also increased the number of adhering melanoma cells; however, this was not affected by IL-1 receptor blockade or TNF neutralization but rather by anti-VCAM-1. These results demonstrate a role for IL-1beta and IL-18 in the development of hepatic metastases of B16M in vivo. In vitro, soluble products from B16M cells stimulate HSE to sequentially release TNF-alpha, IL-1beta, and IL-18. The IL-18 cytokine increases expression of VCAM-1 and the adherence of melanoma cells.

Animals↗

PubMed2000

Interleukin-1beta deficiency results in reduced NF-kappaB levels in pregnant mice.

Interleukin (IL)-1beta-deficient (IL-1beta(-/-)) mice were assessed for cytokine production during pregnancy. A significant reduction in nuclear factor (NF)-kappaB p65 protein content was observed in the uteri and spleens of pregnant IL-1beta(-/-) mice, as demonstrated by immunohistochemistry and Western immunoblot analysis. In addition, electromobility gel shift assay revealed less DNA binding activity of NF-kappaB p65-containing complex in pregnant IL-1beta(-/-) mice. To investigate differences in cytokine production regulated by NF-kappaB, the levels of tumor necrosis factor-alpha, macrophage inflammatory protein-1alpha, and interferon-gamma were measured in the uterine wall, spleen homogenates, and spleen cell cultures obtained from pregnant mice. Endocervical administration of lipopolysaccharide (LPS) increased cytokine levels in both wild-type (IL-1beta(+/+)) and IL-1beta(-/-) animals, but in IL-1beta(-/-) mice this response was 50-75% lower. Splenocytes from nonpregnant mice exhibited decreased LPS-induced cytokine production when primed in vitro with progesterone. This suppression was 25% greater in IL-1beta(-/-) than in IL-1beta(+/+) mice. These data suggest that constitutive NF-kappaB p65 protein synthesis is regulated by IL-1beta, particularly during pregnancy.

Animals↗

PubMed2000

Expression of interleukin-18 in the lung after endotoxemia or hemorrhage-induced acute lung injury.

Hemorrhage and endotoxemia are important risk factors for the development of acute lung injury. Interleukin (IL)-18 is a recently described cytokine released in its mature, active form after pro-IL-18 is cleaved by the IL-1 converting enzyme (ICE). IL-18 has multiple immunomodulating properties, including induction of interferon-gamma (IFN-gamma), IL-1beta, tumor necrosis factor-alpha, and intercellular adhesion molecule-1. To examine the possible involvement of IL-18 in acute lung injury, we examined its expression, as well as that of IFN-gamma, IL-12, and ICE, using murine hemorrhage or endotoxemia models. The amounts of IL-18 messenger RNA (mRNA) increased in the lung after hemorrhage or endotoxemia. However, only endotoxemia was associated with elevations in lung and plasma concentrations of IL-18 protein. ICE expression was increased in the lungs after endotoxemia but not after hemorrhage. Although IFN-gamma expression increased in the lungs after hemorrhage or endotoxemia, elevations in lung IL-12 mRNA levels were found only after endotoxemia. These results indicate that hemorrhage and endotoxemia induce different patterns of immunomodulatory cytokine expression in the lungs. In particular, differences in the expression of ICE after hemorrhage or endotoxemia may affect generation of the active forms of downstream cytokines, including IL-18. IFN-gamma expression in the lungs after hemorrhage appears to occur through a pathway independent of IL-12 and IL-18. IL-18 may play a role in modulating the development of acute lung injury after endotoxemia but not after hemorrhage.

Animals↗

PubMed2000

Interleukin-18 mRNA, but not interleukin-18 receptor mRNA, is constitutively expressed in islet beta-cells and up-regulated by interferon-gamma.

Interleukin-18 (IL-18) mRNA is expressed in islets of NOD mice during the early stages of insulitis and IL-18 has therefore been implicated as a contributing factor in immune-mediated beta-cell destruction. However, a recent study failed to show any effect of human IL-18 on the function of isolated rat islets. Since species differences have been shown between human and murine IL-18, the aims of this study were to investigate 1) if species homologous IL-18 alone or following IL-12 pre-exposure affected rat islet function, 2) if IL-18 dose-dependently modulated IL-1 beta or interferon-gamma (IFN-gamma) + tumor necrosis factor-alpha (TNF-alpha) actions on islet function, and 3) if IL-18 and IL-18 receptor (IL-18R) were expressed in rat islet beta-cells. Insulin release and nitric oxide (NO) production from isolated rat islets were measured after incubation with or without cytokines. RT-PCR was used to quantitate mRNA expression of IL-18 and the IL-18R signaling chain (IL-18R beta). There were no significant effects of 0.625-10 nM recombinant murine (rm) IL-18 alone on accumulated or glucose-challenged insulin release or NO production after 24 hours. Fifteen pg/ml of recombinant human (rh) IL-1 beta as well as 200 U/ml recombinant rat (rr) IFN-gamma + 250 U/ml rhTNF-alpha significantly increased islet NO production and inhibited both accumulated and glucose-challenged islet insulin release. However, rmIL-18 failed to modulate these effects of IL-1 beta or IFN-gamma + TNF-alpha. Although IL-12 induces IL-18R expression in Th1 and B lymphocytes, 24-hours rmIL-12 preincubation neither sensitized islets to effects of 10 nM of rm or rrIL-18 alone nor primed the islets to IL-1 beta actions on insulin release and NO production. IL-18R beta mRNA, which was expressed in human peripheral blood mononuclear cells (PBMC), was not expressed in rat insulinoma (RIN) cells or in isolated rat islets, even after exposure to IL-1 beta and/or IFN-gamma + TNF-alpha or IL-12. IL-18 mRNA was constitutively expressed in RIN cells, in FACS-purified rat beta-cells and in intact rat and mouse islets, and was up-regulated by IFN-gamma in an interferon regulatory factor-1- IRF-1) and NO - independent manner. However, IL-18 protein was undetectable in lysates and supernates of RIN cells by ECL, Western blotting and immunoprecipitation. In conclusion, we show for the first time that IL-18 but not IL-18R is expressed in rodent islet beta-cells. The physiological importance and pathological role of IL-18 originating from islet beta-cells deserve further investigation.

Animals↗

PubMed2000

Leptin in the regulation of immunity, inflammation, and hematopoiesis.

Leptin, the product of the ob gene, is a pleiotropic molecule that regulates food intake as well as metabolic and endocrine functions. Leptin also plays a regulatory role in immunity, inflammation, and hematopoiesis. Alterations in immune and inflammatory responses are present in leptin- or leptin-receptor-deficient animals, as well as during starvation and malnutrition, two conditions characterized by low levels of circulating leptin. Both leptin and its receptor share structural and functional similarities with the interleukin-6 family of cytokines. Leptin exerts proliferative and antiapoptotic activities in a variety of cell types, including T lymphocytes, leukemia cells, and hematopoietic progenitors. Leptin also affects cytokine production, the activation of monocytes/macrophages, wound healing, angiogenesis, and hematopoiesis. Moreover, leptin production is acutely increased during infection and inflammation. This review focuses on the role of leptin in the modulation of the innate immune response, inflammation, and hematopoiesis.

Adaptation, Physiological↗

PubMed1999

Increasing levels of interleukin (IL)-1Ra and IL-6 during the first 2 days of hospitalization in unstable angina are associated with increased risk of in-hospital coronary events.

BACKGROUND: A growing body of evidence suggests a role for inflammation in acute coronary syndromes. The aim of this study was to assess the role of proinflammatory cytokines, their time course, and their association with prognosis in unstable angina. METHODS AND RESULTS: We studied 43 patients aged 62+/-8 years admitted to our coronary care unit for Braunwald class IIIB unstable angina. In each patient, serum levels of interleukin-1 receptor antagonist (IL-1Ra), interleukin-6 (IL-6) (which represent sensitive markers of biologically active IL-1beta and tumor necrosis factor-alpha levels, respectively), and troponin T were measured at entry and 48 hours after admission. Troponin T-positive patients were excluded. Patients were divided a posteriori into 2 groups according to their in-hospital outcome: group 1 comprised 17 patients with an uneventful course, and group 2 comprised 26 patients with a complicated in-hospital course. In group 1, mean IL-1Ra decreased at 48 hours by 12%, and IL-6 diminished at 48 hours by 13%. In group 2, IL-1Ra and IL-6 entry levels were higher than in group 1 and increased respectively by 37% and 57% at 48 hours (P<0.01). CONCLUSIONS: These findings indicate that although they receive the same medical therapy as patients who do not experience an in-hospital event, patients with unstable angina and with complicated in-hospital courses have higher cytokine levels on admission. A fall in IL-1Ra and IL-6 48 hours after admission was associated with an uneventful course and their increase with a complicated hospital course. These findings may suggest novel therapeutic approaches to patients with unstable angina.

Angina, Unstable↗

PubMed1999

Gene expression, synthesis, and secretion of interleukin 18 and interleukin 1beta are differentially regulated in human blood mononuclear cells and mouse spleen cells.

Interleukin (IL)-18, formerly called interferon gamma (IFN-gamma)-inducing factor, is biologically and structurally related to IL-1beta. A comparison of gene expression, synthesis, and processing of IL-18 with that of IL-1beta was made in human peripheral blood mononuclear cells (PBMCs) and in human whole blood. Similar to IL-1beta, the precursor for IL-18 requires processing by caspase 1. In PBMCs, mature but not precursor IL-18 induces IFN-gamma; in whole human blood stimulated with endotoxin, inhibition of caspase 1 reduces IFN-gamma production by an IL-1beta-independent mechanism. Unlike the precursor for IL-1beta, precursor for IL-18 was expressed constitutively in PBMCs and in fresh whole blood from healthy human donors. Western blotting of endotoxin-stimulated PBMCs revealed processed IL-1beta in the supernatants via an caspase 1-dependent pathway. However, in the same supernatants, only unprocessed precursor IL-18 was found. Unexpectedly, precursor IL-18 was found in freshly obtained PBMCs and constitutive IL-18 gene expression was present in whole blood of healthy donors, whereas constitutive IL-1beta gene expression is absent. Similar to human PBMCs, mouse spleen cells also constitutively contained the preformed precursor for IL-18 and expressed steady-state IL-18 mRNA, but there was no IL-1beta protein and no spontaneous gene expression for IL-1beta in these same preparations. We conclude that although IL-18 and IL-1beta are likely members of the same family, constitutive gene expression, synthesis, and processing are different for the two cytokines.

Animals↗

PubMed1999

Interleukin-18 binding protein: a novel modulator of the Th1 cytokine response.

An interleukin-18 binding protein (IL-18BP) was purified from urine by chromatography on IL-18 beads, sequenced, cloned, and expressed in COS7 cells. IL-18BP abolished IL-18 induction of interferon-gamma (IFNgamma), IL-8, and activation of NF-kappaB in vitro. Administration of IL-18BP to mice abrogated circulating IFNgamma following LPS. Thus, IL-18BP functions as an inhibitor of the early Th1 cytokine response. IL-18BP is constitutively expressed in the spleen, belongs to the immunoglobulin superfamily, and has limited homology to the IL-1 type II receptor. Its gene was localized on human chromosome 11q13, and no exon coding for a transmembrane domain was found in an 8.3 kb genomic sequence. Several Poxviruses encode putative proteins highly homologous to IL-18BP, suggesting that viral products may attenuate IL-18 and interfere with the cytotoxic T cell response.

Amino Acid Sequence↗

PubMed1999

Interleukin-18 and interleukin-1 beta: two cytokine substrates for ICE (caspase-1).

This special article deals with the role of processing enzymes in the generation of bioactive cytokines, particularly IL-1 beta and the novel cytokine IL-18, which was formerly called IFN gamma-inducing factor (IGIF). The "classical" pathways of cytokine processing are described, as well as the importance of alternative cleavage enzymes. The topic of this review also concerns the biology of IL-18. The regulation of IL-18 production, the IL-18 receptor complex, and the biological effects of this novel cytokine are described.

Amino Acid Sequence↗

PubMed1999

New insights into the biology of the acute phase response.

Innate or natural immunity is a highly conserved defense mechanism against infection found in all multicellular organisms. The acute phase response is the set of immediate inflammatory responses initiated by pattern recognition molecules. These germ cell-encoded proteins recognize microbial pathogens based on shared molecular structures and induce host responses that localize the spread of infection and enhance systemic resistance to infection. Innate immunity also influences the initiation and type of adaptive immune response by regulating T cell costimulatory activity and antigen presentation by antigen presenting cells and by influencing mediator production, which affects lymphocyte function and trafficking. Acute phase protein concentrations rapidly increase after infection, and their production is controlled primarily by IL-6- and IL-1-type cytokines. The acute phase proteins provide enhanced protection against microorganisms and modify inflammatory responses by effects on cell trafficking and mediator release. For example, serum amyloid A has potent leukocyte activating functions including induction of chemotaxis, enhancement of leukocyte adhesion to endothelial cells, and increased phagocytosis. The constellation of inflammatory responses seen after endotoxin administration to humans represents an in vivo model of the acute phase response. Studies with inflammatory modifying agents, such as soluble dimeric TNF receptor and IL-10, show that these responses are not dependent on a single mediator but result from multiple overlapping inflammatory pathways. Understanding the factors that initiate and alter the magnitude and duration of the acute phase response represents an important step in the development of new therapies for infectious and inflammatory diseases.

Acute-Phase Proteins↗

PubMed1999

Utilization of endoscopic inoculation in a mouse model of intrauterine infection-induced preterm birth: role of interleukin 1beta.

A novel murine model of intrauterine infection/inflammation-induced preterm birth based on direct endoscopic intracervical inoculation is described. Using this model, we investigated infection-induced premature pregnancy loss in normal and interleukin (IL) 1beta-deficient mice. Seventy-four CD-1, HS, C57BL/6J wild type (IL-1beta+/+), and C57BL/6J IL-1beta-deficient (IL-1beta-/-) mice were inoculated intracervically using a micro-endoscope, at a time corresponding to 70% of average gestation. Intracervical injection of lipopolysaccharide (LPS) or Escherichia coli reliably induced premature birth: 100% of mice intracervically injected with LPS and 92% of mice with a positive endometrial E. coli culture delivered prematurely within 36 h after inoculation. No losses were observed in mice inoculated with saline. Pregnancy loss was associated with increased uterine tissue cyclooxygenase-2 gene expression and uterine content of IL-1beta, tumor necrosis factor alpha, macrophage inflammatory protein-1alpha, and IL-6, as well as elevation of nuclear factor-kappaB activity in uterine tissues. Although IL-1beta-/- mice exhibited decreased uterine cytokine production in response to bacteria and LPS, IL-1beta deficiency did not affect the rate of pregnancy loss. This model using direct intracervical bacterial or LPS inoculation is useful for studying preterm pregnancy loss in genetically altered mice in order to develop novel interventions for infection-associated preterm labor.

Animals↗

PubMed1999

Effects of lisofylline on hyperoxia-induced lung injury.

Lisofylline [1-(5R-hydroxyhexyl)-3,7-dimethylxanthine] decreases lipid peroxidation in vitro and in vivo suppresses proinflammatory cytokine expression in models of lung injury due to sepsis, blood loss, and oxidative damage. In the present experiments, we used a murine hyperoxia model to examine the effects of lisofylline on the activation of nuclear transcriptional regulatory factors [nuclear factor-kappaB and cAMP response element binding protein (CREB)], the expression of proinflammatory cytokines in the lungs, and the circulating levels of oxidized free fatty acids as well as on hyperoxia-induced lung injury and mortality. Treatment with lisofylline inhibited hyperoxia-associated increases in tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 in the lungs as well as decreased the levels of hyperoxia-induced serum-oxidized free fatty acids. Although hyperoxic exposure produced activation of both nuclear factor-kappaB and CREB in lung cell populations, only CREB activation was reduced in the mice treated with lisofylline. Lisofylline diminished hyperoxia-associated increases in lung wet-to-dry weight ratios and improved survival in animals exposed to hyperoxia. These results suggest that lisofylline ameliorates hyperoxia-induced lung injury and mortality through inhibiting CREB activation, membrane oxidation, and proinflammatory cytokine expression in the lungs.

Animals↗

PubMed1999

Leptin deficiency enhances sensitivity to endotoxin-induced lethality.

Leptin is induced by lipopolysaccharide (LPS) and cytokines. We investigated the role of leptin in LPS-induced toxicity using leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) mice. Sensitivity to LPS-induced mortality is significantly greater in ob/ob mice compared with their own lean littermates but not in db/db mice. LPS reduced serum glucose in both ob/ob and db/db mice but induced corticosterone only in db/db mice. Despite the very high basal levels of serum leptin in db/db mice, a twofold increase in serum leptin levels was observed after LPS in both db/db mice and their lean littermates. No differences were detected in LPS-induced serum levels of interleukin (IL)-1beta, tumor necrosis factor, macrophage inflammatory protein-1alpha, and interferon-gamma in ob/ob mice compared with their own littermates. In contrast, a blunted induction of IL-10 and IL-1 receptor antagonist (IL-1Ra) was observed in ob/ob mice compared with their littermates. In vitro, leptin induced IL-1Ra production and upregulated the IL-1Ra induction by LPS in macrophages. Moreover, treatment with leptin reversed the increased sensitivity to LPS-induced lethality found in ob/ob mice. These results suggest that leptin participates in the host response to inflammation by modulating the host immune and cytokine responses after LPS.

Animals↗

PubMed1999

IL-12-induced IFN-gamma is dependent on caspase-1 processing of the IL-18 precursor.

IL-12 and IL-18 are IFN-gamma-inducing cytokines. In the present study, the role of endogenous IL-18 in the induction of IFN-gamma by IL-12 was investigated in mice. In the presence of a specific inhibitor of caspase-1 (also known as IL-1beta-converting enzyme, or ICE) IL-12-induced IFN-gamma from splenocytes was reduced by 85%. Using splenocytes from ICE-deficient mice, IL-12-induced IFN-gamma was reduced by 80%. However, the role of ICE was not through processing and release of IL-1beta. Neutralizing anti-IL-18 IgG reduced IL-12-induced IFN-gamma in splenocytes by 85%. Splenocytes cultured in vitro spontaneously released IL-18 into the extracellular compartment over time. Extracellular levels of IL-18 significantly correlated with IL-12-induced IFN-gamma and were reduced in cells obtained from ICE-deficient mice. In vivo, IL-12 administration increased circulating levels of IL-18 in wild-type mice but not in ICE-deficient mice. Both neutralization of IL-18 and ICE deficiency significantly reduced induction of circulating IFN-gamma in mice receiving IL-12. The IL-18 precursor was constitutively expressed in the livers and spleens of untreated mice. Furthermore, administration of IL-12 significantly increased liver-associated IL-18 levels. These data demonstrate that endogenous, ICE-cleaved IL-18 significantly contributes to induction of IFN-gamma by IL-12.

Animals↗

PubMed1999

Elevated circulating levels of soluble interleukin-1 receptor type II during interleukin-2 immunotherapy.

Interleukin-1 (IL-1) is a critical mediator of inflammation. Two naturally occurring IL-1 antagonists have been described, namely the IL-1 receptor antagonist (IL-1Ra) and the IL-1 receptor type II (IL-1RII). IL-1RII does not transmit a signal upon binding of IL-1, but competes with the signaling of IL-1RI for binding of IL-1. Shedding of IL-1RII yields the soluble IL-1 receptor type II (IL-1sRII) which retains the ability of membrane-bound IL-1RII to bind IL-1beta avidly, but binds IL-1Ra and IL-1alpha with low affinity. In contrast, IL-1sRI retains the ability of membrane-bound IL-1RI to bind IL-1Ra and IL-1alpha with high affinity, but binds IL-1beta poorly. We have previously shown that immunotherapy with IL-2 or IL-6 in cancer patients is associated with a dramatic increase in IL-1Ra plasma levels. In the present study, plasma levels of soluble IL-1 receptors were monitored in healthy individuals and cancer patients. In healthy controls, the mean IL-1sRII level was 4.76 0.16 ng/ml. IL-1sRII levels in cancer patients were comparable to those measured in healthy controls. IL-1sRII levels did not vary during the first 52 hours after initiation of IL-2 therapy, but increased significantly thereafter to reach 9.56 1.16 ng/ml on day 5. In contrast, IL-6 immunotherapy with a 5-day continuous infusion did not trigger an increase in IL-1sRII levels. IL-1sRI levels did not increase during immunotherapy with IL-2 or IL-6. Our results indicate that IL-1sRII, unlike IL-1Ra, remains a modest, natural, anti-inflammatory mechanism triggered by immunotherapy with IL-2, but not with IL-6.

Carcinoma, Renal Cell↗

PubMed1998

Blood and breath analyses as biological indicators of exposure to trihalomethanes in indoor swimming pools.

In this article, exposure to trihalomethanes (THMs) in indoor swimming pools as a consequence of water chlorination is reported. Environmental and biological monitoring of THMs was performed in order to assess the uptake of these substances after a defined period in five competitive swimmers, regularly attending an indoor swimming pool to train for competition during four sampling sessions. Analyses were performed by gas-chromatography and the following THMs were detected: chloroform (CHC13), bromodichloromethane (CHBrC12), dibromochloromethane (CHBrsC1) and bromoform (CHBr3). CHC13 appeared the most represented compound both in water and in environmental air before and after swimming. CHBrC1w and CHBr2C1 were always present, even though at lower levels than CHC13, CHBr3, was rarely present. In relation to biological monitoring, CHC13, CHBrC12 and CHBr2C1 were detected in all alveolar air samples collected inside the swimming pool. Before swimming, after 1 h at rest at the pool edge, the mean values were 29.4 +/- 13.3, 2.7 +/- 1.2 and 0.8 +/- 0.8 micrograms/m3, respectively, while after spending 1 h swimming, higher levels were detected (75.6 +/- 18.6, 6.5 +/- 1.3 and 1.4 +/- 0.9 micrograms/m3, respectively). Only CHC13 was detected in all plasma samples (mean: 1.4 +/- 0.5 micrograms/1) while CHBrC1x and CHBr2C1 were observed only in few samples at a detection limit of 0.1 micrograms/1. After 1 h at rest, at an average environmental exposure of approx. 100 micrograms/m3, the THM uptake was approx. 30 micrograms/h (26 micrograms/h for CHC1c, 3 micrograms/h for CHBrC12 and 1.5 micrograms/h for CHBr2C1). After 1 h swimming, the THM uptake is approx. seven times higher than at rest: a THM mean uptake of 221 micrograms/h (177 micrograms/h, 26 micrograms/h and 18 micrograms/h for CHC13, CHBrC12 and CHBr2C1, respectively) was evaluated at an environmental concentration of approx. 200 micrograms/m3.

Adolescent↗

PubMed1998

Interleukin-18 regulation of interferon gamma production and cell proliferation as shown in interleukin-1beta-converting enzyme (caspase-1)-deficient mice.

Interleukin-18 (IL-18) is a costimulatory factor for interferongamma (IFNgamma) production. Processing of pro-IL-18 by IL-1beta-converting enzyme (ICE) leads to the release of bioactive IL-18. Compared with wild-type (WT) mice, splenocytes from ICE-deficient mice produced low IFNgamma after lipopolysaccharide (LPS) or zymosan (50% and 80% reduction). In contrast, IFNgamma production was unimpaired in ICE-deficient mice using Concanavalin A (Con A). Comparable results were obtained when endogenous IL-18 was blocked with a neutralizing antibody. LPS-induced IFNgamma was also reduced by an ICE inhibitor. Exogenous IL-18 augmented zymosan-induced IFNgamma production in WT mice. In ICE-deficient cells, IFNgamma production was only partially restored by IL-18. The reduced levels of IFNgamma in ICE-deficient mice were not due to a lack of IL-12, because zymosan induced IL-12 equally in WT and in ICE-deficient mice. IFNgamma is an important regulator of cell proliferation. In accordance, splenocytes from ICE-deficient mice proliferated more when stimulated with LPS, but not with Con A. Furthermore, in ovalbumin-sensitized ICE-deficient mice, proliferation of lymph node cells in response to the specific antigen was not altered. Exogenous IFNgamma inhibited, whereas blockade of endogenous IFNgamma or IL-18 increased, LPS induced splenocyte proliferation both in WT and in ICE-deficient mice. Our results show that IL-18 is an IL-12-independent regulator of IFNgamma production and of cell proliferation induced by microbial stimuli. However, ICE-dependent processing of IL-18 is not needed for response to mitogens or antigens.

Animals↗