Biomedical subjects

G Fantuzzi

Publications and source records attributed to G Fantuzzi.

At least 55 records · Page 3Linked to original sources

PubMed1998

Interleukin-18 (IFNgamma-inducing factor) induces IL-8 and IL-1beta via TNFalpha production from non-CD14+ human blood mononuclear cells.

IL-18 is synthesized as a precursor molecule without a signal peptide but requires the IL-1beta converting enzyme (ICE, caspase-1) for cleavage into a mature peptide. Human precursor IL-18 was expressed, purified, and cleaved by ICE into a 18-kD mature form. Mature IL-18 induced IL-8, macrophage inflammatory protein-1alpha, and monocyte chemotactic protein-1 in human peripheral blood mononuclear cells in the absence of any co-stimuli. Blocking IL-1 with IL-1 receptor antagonist resulted in a 50% reduction in IL-8. Neutralization of TNF with TNF binding protein resulted in a 66% reduction in IL-1beta, an 80% reduction of IL-8, and an 88% reduction in mean TNFalpha mRNA. In purified CD14+ cells but not CD3+/CD4+, IL-18 induced gene expression and synthesis of IL-8 and IL-1beta. TNFalpha production was induced in the non-CD14+ population and there was no induction of TNFbeta by IL-18. In purified natural killer cells, IL-18 induced IL-8 that was also inhibited by TNF binding protein. IL-18 did not induce antiinflammatory cytokines, IL-1Ra, or IL-10, although IL-18 induction of TNFalpha was inhibited by IL-10. In the presence of IFNgamma, IL-18-induced TNFalpha was enhanced and there was an increase in the mature form of IL-1beta. We conclude that IL-18 possesses proinflammatory properties by direct stimulation of gene expression and synthesis of TNFalpha from CD3+/CD4+ and natural killer cells with subsequent production of IL-1beta and IL-8 from the CD14+ population.

CD3 Complex↗

PubMed1998

Interleukin-18 enhances lipopolysaccharide-induced interferon-gamma production in human whole blood cultures.

Interleukin-18 (IL-18) is a newly described cytokine, formerly called interferon-gamma (IFN-gamma)-inducing factor. In a simple 24-h human whole blood culture, IFN-gamma was produced by the combination of lipopolysaccharide (LPS) plus IL-18. To liberate cytokines in the leukocyte and red cell compartments, the detergent Triton X-100 was added to the entire blood culture. The combination of low concentrations of LPS plus IL-18 induced a 3- to 5-fold greater production of IFN-gamma than did either stimulant alone. Tumor necrosis factor-alpha (TNF-alpha), IL-6, and IL-8 were also produced. The presence of IL-10 completely suppressed the production of IFN-gamma and reduced that of TNF-alpha, IL-6, and IL-8. Thus, IFN-gamma, TNF-alpha, IL-8, and IL-6 are produced in a single whole blood culture, making correlations in the synthesis of a T helper type 1 cytokine and proinflammatory cytokines with disease activity possible in a single culture.

Adult↗

PubMed1998

Spontaneous and inducible cytokine responses in healthy humans receiving a single dose of IFN-alpha2b: increased production of interleukin-1 receptor antagonist and suppression of IL-1-induced IL-8.

The present study was to determine whether the administration of a single dose of interferon-alpha2B (IFN-alpha2B) to healthy humans affects endogenous (or basal level) or inducible cytokines in a whole blood, ex vivo culture. Twenty-four healthy volunteers received an s.c. injection of IFN-alpha2b (3 x 10(6)U), and 4 volunteers received the vehicle as placebo. The study was blinded. Blood was drawn before and 3, 6, 12, and 24 h after the injection and incubated in the presence or absence of lipopolysaccharide (LPS) or interleukin-1beta (IL-1beta). After 24 hs, the plasma was assayed for tumor necrosis factor-alpha (TNF-alpha), IFN-gamma, IL-1beta, IL-1 receptor antagonist (IL-1Ra), and IL-8. Treatment with IFN-alpha2b was associated with a 4.8-fold increase in the endogenous production of IL-1Ra in cultured blood sustained over 24 hs. In contrast, no change in endogenous IL-1Ra production was detected in the controls. A significant suppression (75%, p < 0.001) of IL-1beta-induced IL-8 production 3 and 6 h after IFN-alpha2b compared with control subjects was observed. These effects were also observed when IFN-alpha2b was added directly to whole blood cultures in vitro. In contrast to IL-1 stimulation, LPS stimulation of blood from IFN-alpha2b-treated subjects resulted in enhanced IL-1beta and TNF-alpha production. These results suggest that a single dose of IFN-alpha2b induces an anti-inflammatory state for endogenous stimuli but a proinflammatory state for exogenous endotoxin.

Adult↗

PubMed1998

IL-1 beta mediates leptin induction during inflammation.

Interleukins (IL) are key mediators of the host response to infection and inflammation. Leptin is secreted by adipose tissue and plays an important role in the control of food intake. Administration of lipopolysaccharide (LPS), tumor necrosis factor (TNF), or IL-1 acutely increases leptin mRNA and protein levels. To investigate the role of IL-1 beta and IL-6 in leptin expression during inflammation, we used IL-1 beta-deficient (-/-) and IL-6 -/- mice. Mice were injected intraperitoneally with LPS or subcutaneously with turpentine, as models of systemic or local inflammation, respectively. In IL-1 beta +/+ mice, both LPS and turpentine increased leptin mRNA and circulating leptin. In contrast, neither LPS nor turpentine increased leptin levels in IL-1 beta -/- mice. In IL-6 +/+ or IL-6 -/- mice, turpentine increased leptin protein to comparable levels. We conclude that IL-1 beta is essential for leptin induction by both LPS and turpentine in mice, but IL-6 is not.

Animals↗

PubMed1998

Stem cell factor-deficient mice have a dysregulation of cytokine production during local inflammation.

We have studied the responses of stem cell factor-deficient (SCF-) mice in two models of local inflammation, turpentine-induced tissue damage and zymosan-induced peritonitis. These mice have a profound mast cells deficiency. Following administration of either zymosan or turpentine, SCF- mice developed a more severe body weight loss than wild type (SCF+) mice. An exaggerated systemic production of interleukin-1beta (IL-1beta) and IL-6 was observed in SCF- mice. However, systemic tumor necrosis factor-alpha (TNF-alpha) levels were undetectable in SCF- mice following zymosan administration. The peritoneal lavage fluid (PLF) of SCF- mice also showed a marked increase in IL-1beta following zymosan administration, whereas local IL-6 and TNF-alpha production were not affected. In addition, PLF levels for the chemokine MIP-1alpha were strongly reduced in SCF- mice. This was associated with a reduced number of infiltrating cells. A possible mechanism for these differences was a reduction in IL-4 production in SCF- mice. Both local and systemic levels for IL-4 were significantly lower in SCF- mice following either zymosan or turpentine administration. Our results suggest that mast cells and/or SCF are important regulators of the production of cytokines in the course of inflammatory responses.

Animals↗

PubMed1998

Overview of interleukin-18: more than an interferon-gamma inducing factor.

Initially described in 1989 as interferon-gamma (IFN-gamma) inducing factor (IGIF), interleukin-18 (IL-18) is a novel pro-inflammatory cytokine that is clearly more than an inducer of IFN-gamma. The cytokine possesses several biological properties such as activation of nuclear factor-kappaB (NF-kappaB), Fas ligand expression, the induction of both CC and CXC chemokines, and increased production of competent human immunodeficiency virus. Most activities are due to a receptor complex that recruits the IL-1 receptor-activating kinase (IRAK), leading to translocation of NF-kappaB. This property and others support the concept that IL-18 is related to the IL-1 family. Indeed, one of the IL-18 receptor chains is the IL-1 receptor-related protein, a member of the IL-1R family. In addition, IL-18 is structurally similar to IL-1beta and like IL-1beta is first synthesized as a leaderless precursor requiring the IL-1beta converting enzyme for cleavage into an active molecule. The biology of IL-18 is reviewed in the overview and the implication for a role for this cytokine in disease is presented.

Animals↗

PubMed1997

Mouse IL-1 receptor antagonist isoforms: complementary DNA cloning and protein expression of intracellular isoform and tissue distribution of secreted and intracellular IL-1 receptor antagonist in vivo.

IL-1R antagonist (IL-1Ra) is a competitive inhibitor of the binding of IL-1 to IL-1R. IL-1Ra refers to two different proteins derived from the same gene by alternate splicing of two different first exons. One protein contains a leader sequence and is secreted (sIL-1Ra), whereas the other remains intracellular (icIL-1Ra). We describe the cloning of mouse icIL-1Ra cDNA, the expression of the recombinant mouse icIL-1Ra protein, and the tissue distribution of sIL-1Ra and icIL-1Ra mRNA and of icIL-1Ra protein in control and LPS-injected mice. As described in the human and the rabbit, mouse icIL-1Ra protein differs from mature mouse sIL-1Ra protein by seven amino acids at the amino terminus. In addition, human and mouse icIL-1Ra are 77% identical. Regulation of IL-1Ra isoforms was examined in normal mice and after LPS injection. Circulating levels were undetectable in control mice, but were strongly increased 4 h after LPS injection. Using a ribonuclease protection assay (RPA), we found that icIL-1Ra mRNA was expressed constitutively in skin and in LPS-stimulated RAW 264.7 murine macrophages. Consistent with the RNA studies, Western blot analysis showed that murine icIL-1Ra protein was constitutively expressed in skin and in LPS-stimulated RAW 264.7 cells. In contrast, sIL-1Ra mRNA was not detected by RPA in tissues of control mice, but was strongly up-regulated in the lung, spleen, and liver after LPS injection. Using RPA, primer extension assay and 5' rapid amplification of cDNA ends, we were able to demonstrate the presence of different transcription start sites for murine sIL-1Ra mRNA.

Alternative Splicing↗

PubMed1997

Hemorrhage increases cytokine expression in lung mononuclear cells in mice: involvement of catecholamines in nuclear factor-kappaB regulation and cytokine expression.

The expression of proinflammatory and immunoregulatory cytokines rapidly increases in the lungs after hemorrhage, and such alterations contribute to the frequent development of acute inflammatory lung injury in this setting. Blood loss also produces elevations in catecholamine concentrations in the pulmonary and systemic circulation. In the present experiments, we used alpha- and beta-adrenergic receptor blockade to examine in vivo interactions between hemorrhage-induced adrenergic stimulation and pulmonary cytokine expression. Treatment of mice with the alpha-adrenergic receptor antagonist phentolamine prevented not only the elevation in mRNA levels of IL-1beta, TNF-alpha, and TGF-beta1, the increase in IL-1beta protein, but also the activation of nuclear factor (NF)-KB and cyclic AMP response element binding protein, which occurred in lung cells of untreated animals during the first hour after hemorrhage. In contrast, treatment before hemorrhage with the beta-adrenergic receptor antagonist propranolol was associated with increases in mRNA levels for IL-1beta, TNF-alpha, and TGF-beta1, which were greater than those present in untreated hemorrhaged mice, and did not prevent hemorrhage-associated increases in lung IL-1beta protein. Treatment with propranolol prevented hemorrhage-induced phosphorylation of cyclic AMP response element binding protein, but increased hemorrhage-associated activation of NF-KB. These results demonstrate that hemorrhage initially increases pulmonary cytokine expression through alpha- but not beta-adrenergic stimulation, and suggest that such alpha-adrenergic-mediated effects occur through activation of the transcriptional regulatory factor NF-kappaB.

Animals↗

PubMed1997

Hyperresponsive febrile reactions to interleukin (IL) 1alpha and IL-1beta, and altered brain cytokine mRNA and serum cytokine levels, in IL-1beta-deficient mice.

IL-1beta is an endogenous pyrogen that is induced during systemic lipopolysaccharide (LPS)- or IL-1-induced fever. We have examined the fever and cytokine responses following i.p. injection of IL-1 agonists, IL-1alpha and IL-1beta, and compared these with response to LPS (i.p.) in wild-type and IL-1beta-deficient mice. The IL-1beta deficient mice appear to have elevated body temperature but exhibit a normal circadian temperature cycle. Exogenously injected IL-1beta, IL-1alpha, or LPS induced hyperresponsive fevers in the IL-1beta-deficient mice. We also observed phenotypic differences between wild-type and IL-1beta-deficient mice in hypothalamic basal mRNA levels for IL-1alpha and IL-6, but not for IL-1beta-converting enzyme or IL-1 receptor type I or type II. The IL-1alpha mRNA levels were down-regulated, whereas the IL-6 mRNA levels were up-regulated in the hypothalamus of IL-1beta-deficient mice as compared with wild-type mice. The IL-1beta-deficient mice also responded to LPS challenge with significantly higher serum corticosterone and with lower serum tumor necrosis factor type alpha levels than the wild-type mice. The data suggest that, in the redundant cascade of proinflammatory cytokines, IL-1beta plays an important but not obligatory role in fever induction by LPS or IL-1alpha, as well as in the induction of serum tumor necrosis factor type alpha and corticosterone responses either by LPS or by IL-1alpha or IL-1beta.

Animals↗

PubMed1997

Response to local inflammation of IL-1 beta-converting enzyme- deficient mice.

IL-1 beta-converting enzyme (ICE) cleaves pro-IL-1 beta to the mature, released form. Although other proteases can process pro-IL-1 beta, ICE-deficient (ICE -/-) mice do not release mature IL-1 beta in response to endotoxin. The purpose of our study was to investigate the response of ICE -/- mice in two models of local inflammation, turpentine-induced tissue damage and zymosan-induced peritonitis. No differences were observed in the development of the systemic acute phase response after turpentine administration between wild-type and ICE -/- mice, but this response was completely impaired in IL-1 beta -/- mice. Accordingly, the levels of mature IL-1 beta produced in response to turpentine did not differ between wild-type and ICE -/- mice. In contrast, following zymosan-induced peritonitis, the levels of mature IL-1 beta were significantly lower in ICE -/- mice. This was associated with a 50% decrease in cellular infiltrate in ICE -/- mice compared with that in wild-type controls. The reduced production of zymosan-induced mature IL-1 beta in ICE -/- mice was also observed from cultured peritoneal or spleen cells. Our results demonstrate that in turpentine-induced tissue necrosis, precursor IL-1 beta is processed by non-ICE proteases, but in complement-mediated inflammation, ICE participates in the processing of the IL-1 beta precursor.

Animals↗

PubMed1997

Physiological and cytokine responses in IL-1 beta-deficient mice after zymosan-induced inflammation.

Interleukin (IL)-1 beta-deficient (IL-1 beta -/-) mice exhibited decreased zymosan-induced lethality and reduced production of IL-6 compared with wild-type controls (IL-1 beta +/+). In addition, IL-1 beta -/- mice had a diminished cellular infiltrate (33%) in the peritoneal cavity after zymosan. However, anorexia and hypoglycemia were not affected by the lack of IL-1 beta. The induction of corticosterone was only slightly reduced (14%) in IL-1 beta -/- mice. Peritoneal lavage fluid levels for IL-1 alpha, but not for tumor necrosis factor (TNF)-alpha, were also decreased. To evaluate the role of residual IL-1 alpha production in IL-1 beta -/- mice, we used IL-1-receptor antagonist (IL-1ra). In IL-1 beta +/+ mice, IL-1ra inhibited production of IL-6 after zymosan, without affecting TNF-alpha synthesis. There was no further inhibitory effect of IL-1ra on IL-6 production in IL-1 beta -/- mice, suggesting no role for IL-1 alpha in zymosan-induced IL-6. Our results demonstrate that IL-1 beta plays a significant, although not exclusive, role in the physiological and cytokine responses to zymosan-mediated inflammation.

Analysis of Variance↗

PubMed1996

TNF receptor p55 plays a major role in centrally mediated increases of serum IL-6 and corticosterone after intracerebroventricular injection of TNF.

The aim of this work was to study the relative role of the two TNF receptors (p55 and p75) in the central actions of TNF, studying the elevation of serum corticosterone (CS) and IL-6 levels after injection of recombinant murine (rm)TNF (intracerebroventricularly (i.c.v.)) in normal or p55-deficient (p55 -/-) mice. rmTNF induced high serum IL-6 levels and doubled serum CS in normal mice, whereas no elevation of serum IL-6 or CS was induced in p55 -/- mice. However, a normal CS response was observed in p55 -/- mice after LPS (2.5 microg, i.c.v.). p55 -/- mice also responded, although to a lesser extent than p55 +/+, in terms of LPS-induced IL-6 production. We also injected two agonist Abs specific for the two receptors, alpha p55 and alpha p75. While alpha p55 injected i.c.v. induced a marked elevation in CS and IL-6, alpha p75 induced CS (although less than alpha p55) but no IL-6. rmTNF, which binds both receptors, was more potent in inducing IL-6 and CS than injection of rhTNF, which in mice binds only p55. Finally, we investigated the role of p55 and p75 in IL-6 induction by TNF in a murine brain endothelioma. The results resembled closely those obtained in vivo: rmTNF was more potent than rhTNF and only alpha p55, and not alpha p75, induced IL-6 production. These data indicate that p55 plays a major role in TNF activation of the hypothalamus-pituitary-adrenal axis and in the centrally mediated induction of peripheral IL-6 by TNF, but p75, despite having little IL-6 inductive properties by itself, seems to potentiate p55 induction of IL-6.

Animals↗

PubMed1996

Indoor air quality in the university libraries of Modena (Italy).

We carried out a survey in 16 libraries of the University of Modena, Northern Italy, to assess the indoor exposure to volatile organic compounds (VOCs), including formaldehyde, and total dusts. Data were collected on the main structural characteristics of the buildings; indoor microclimate parameters, such as temperature, relative humidity and ventilation rate were measured and air samples taken inside and outside the libraries. The mean value of total dusts was 190 +/- 130 microg/m3 with a wide range of values. Formaldehyde was found in only ten out of 16 libraries and the indoor concentrations ranged from 1.70 to 67.8 microg/m3 with an average value of 32.7 +/- 23.9 microg/m3. On the whole, VOCs were present in all the libraries investigated with an average value was 433 +/- 267 microg/m3 (range 102-936 microg/m3). No correlation was found among VOCs, formaldehyde and total dusts nor was a significant association observed with microclimatic parameters or the structural characteristics of the buildings. The general situation found in this study suggests no major problems related to indoor pollution. However, some of the pollutants investigated such as total dust and total VOCs deserve further investigation. It is important to identify the possible sources of contaminants and to define the relationship between indoor and outdoor levels of pollutants more accurately, taking into account the effects of air recycling due to natural ventilation systems.

Air Pollution, Indoor↗

PubMed1996

Effect of endotoxin in IL-1 beta-deficient mice.

IL-1 plays an important role in the pathophysiologic responses to infection and inflammation, in part by mediating its own production and that of other proinflammatory cytokines. However, the relative contribution of IL-1 alpha and IL-1 beta to the inflammatory response has not been well clarified. Using IL-1 beta-deficient (IL-1 beta -/-) mice, we investigated the specific role of IL-1 beta in the in vivo and in vitro response to LPS. No differences between IL-1 beta +/+ and IL-1 beta -/- mice were observed in circulating levels for IL-1 alpha, IL-6, or TNF-alpha after the systemic administration of either a low (5 micrograms/kg) or high (5 mg/kg) dose of LPS. IL-1 beta -/- mice also had a normal response to LPS in terms of activation of the hypothalamus-pituitary-adrenal axis, hypoglycemia, serum amyloid A production, and anorexia. IL-1 beta -/- mice were normally sensitive to the lethal effect of LPS and were protected against LPS toxicity when pretreated with low-dose LPS. However, in vitro, peritoneal macrophages from IL-1 beta -/- mice stimulated with LPS produced significantly less IL-1 alpha than macrophages from IL-1 beta +/+ mice (p < 0.05). No differences in IL-6 or TNF-alpha synthesis were observed between macrophages from IL-1 beta +/+ and IL-1 beta -/- mice. In summary, our results suggest that either IL-1 beta is not essential for the in vivo systemic response to LPS or that its role can be fulfilled by other cytokines with overlapping activities.

Animals↗

PubMed1996

Six different cytokines that share GP130 as a receptor subunit, induce serum amyloid A and potentiate the induction of interleukin-6 and the activation of the hypothalamus-pituitary-adrenal axis by interleukin-1.

Ciliary neurotrophic factor (CNTF) and interleukin-6 (IL-6) potentiate the elevation of serum corticosterone induced by suboptimal doses of interleukin-1 (IL-1). CNTF also potentiates IL-1-induced serum IL-6. Here, we report that four other cytokines (leukemia inhibitory factor [LIF], oncostatin M [OSM], interleukin-11 and cardiotrophin-1) also potentiated the elevation of serum corticosterone and IL-6 levels induced by IL-1. Furthermore, all the six cytokines studied induced the acute-phase protein serum amyloid A when administered alone. Because these cytokines differ both in structure and in function, but share gp130 as a subunit of their receptors, these results indicate that signaling through gp130 mediates potentiation of IL-1 activities. The potentiation of IL-1-induced serum corticosterone levels is not a consequence of the increased serum IL-6 observed after IL-1 administration. In fact, in IL-6 deficient mice, IL-1 increased serum corticosterone to a level comparable to that observed in wild-type mice. Thus, either endogenous IL-6 does not mediate IL-1-induced corticosterone increase, or its role may be fulfilled by other cytokines. To the extent that gp130-dependent cytokines may serve this role, they may be important feedback regulators of inflammation through the activation of the hypothalamus-pituitary-adrenal axis and the potentiation of acute-phase protein synthesis.

Acute-Phase Reaction↗

PubMed1996

The inflammatory response in interleukin-1 beta-deficient mice: comparison with other cytokine-related knock-out mice.

Interleukin-1 (IL-1) plays a crucial role in the development of the pathophysiological responses to infection and inflammation. However, the relative contributions of IL-1 alpha and IL-1 beta remain to be clarified. IL-1 beta-deficient mice are a powerful tool to investigate the specific role of IL-1 beta in various experimental conditions. In this report, we summarize the response of IL-1 beta deficient mice to two different inflammatory stimuli, turpentine and endotoxin. Although IL-1 beta-deficient mice respond normally to the systemic administration of lipopolysaccharide (LPS), they do not develop an acute-phase response in the localized tissue damage model of turpentine injection. The results obtained using the IL-1 beta-deficient mice are compared here with those observed in the IL-1 beta-converting enzyme-deficient, IL-6-deficient, tumour necrosis factor-receptor p55-deficient, and interferon-gamma-receptor-deficient mice.

Animals↗

PubMed1995

Role of the hypothalamus-pituitary-adrenal axis in the regulation of TNF production in mice. Effect of stress and inhibition of endogenous glucocorticoids.

Glucocorticoids (GC) are known inhibitors of TNF production and are increased by endotoxin (LPS) through a stimulation of the hypothalamus-pituitary-adrenal axis (HPAA), suggesting a feedback mechanism. We tried different approaches to study the role of the HPAA and endogenous GC in the regulation of TNF production. Cyanoketone, a GC synthesis inhibitor, inhibited corticosterone (CS) induction by LPS and increased LPS-induced serum TNF levels. Similar results were obtained by pretreating mice with anticorticotropin-releasing hormone Abs. Administration of adrenocorticotropic hormone increased blood CS and inhibited LPS-induced serum TNF. TNF production by mouse blood stimulated in vitro with LPS was inhibited by addition of CS. Blood from stressed or adrenocorticotropic-releasing hormone-treated mice (in which CS levels are elevated) stimulated ex vivo with LPS produced significantly less TNF than blood from control mice. Normal TNF production was restored by the addition of the GC receptor antagonist RU 38486, indicating a role for the elevated endogenous CS levels in the inhibition of TNF production. These data indicate that the HPAA is a major regulator of TNF production.

Adrenocorticotropic Hormone↗

PubMed1995

Environmental and biological monitoring of chloroform in indoor swimming pools.

The presence of chloroform as the result of disinfection with sodium hypochlorite was demonstrated in the water and ambient air of indoor swimming pools. Environmental monitoring was performed in 12 indoor swimming pools in northern Italy and the level of human exposure was assessed. Biological monitoring performed by gas chromatography on human plasma and alveolar air samples evidenced that the uptake of chloroform in swimmers varies according to the intensity of the physical activity and age. The elimination of chloroform in alveolar air in one subject showed a very short half-life (from 20 to 27 min) and a complete clearance within 10 h after the end of exposure.

Breath Tests↗