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Biomedical subjects

M G Netea

Publications and source records attributed to M G Netea.

At least 55 records · Page 3Linked to original sources
PubMed1999

[Cytokines and immunotherapy in infectious diseases].

Cytokines are essential mediators in infection and inflammation. Almost all cytokines have not only positive but also noxious effects: the proinflammatory cytokines released during severe infections in high concentrations lead to organ damage and death. The antagonistic anti-inflammatory cytokines inhibit the defense against infections. Immunotherapy through modulation of the cytokine response may aim at inhibition of the proinflammatory and reinforcement of the anti-inflammatory cytokine response, so as to limit the damage of inflammation. In patients with sepsis this has so far been little successful, probably owing to the multiple effects of the cytokines. Inhibition of proinflammatory cytokines was successful, on the other hand, in patients with rheumatoid arthritis or Crohn's disease. Another possibility is to aim, on the contrary, at reinforcement of the proinflammatory and inhibition of the anti-inflammatory cytokine response, to strengthen the resistance of the host. This has given favourable results in a limited number of infections.

Adjuvants, Immunologic↗
PubMed1999

Increased susceptibility of TNF-alpha lymphotoxin-alpha double knockout mice to systemic candidiasis through impaired recruitment of neutrophils and phagocytosis of Candida albicans.

TNF-alpha and lymphotoxin-alpha (LT) are members of the TNF family, and these cytokines play crucial roles in the defense against infection with Candida albicans. The aim of the present study was to investigate the role of endogenous TNF and LT during disseminated candidiasis in TNF-/-LT-/- knockout mice. The TNF- and LT-deficient animals had a significantly increased mortality following C. albicans infection compared with control mice, and this was due to a 10- to 1000-fold increased outgrowth of the yeast in their organs. No differences between TNF-/-LT-/- mice and TNF+/+LT+/+ were observed when mice were rendered neutropenic, suggesting that activation of neutrophils mediates the beneficial effects of endogenous TNF and LT. Histopathology of the organs, combined with neutrophil recruitment experiments, showed a dramatic delay in the neutrophil recruitment at the sites of Candida infection in the TNF-/-LT-/- mice. Moreover, the neutrophils of deficient animals were less potent to phagocytize Candida blastospores than control neutrophils. In contrast, the killing of Candida and the oxygen radical production did not differ between neutrophils of TNF-/-LT-/- and TNF+/+LT+/+ mice. Peak circulating IL-6 was significantly higher in TNF-/-LT-/- mice during infection. Peritoneal macrophages of TNF-/-LT-/- mice did not produce TNF, and synthesized significantly lower amounts of IL-1alpha, IL-1beta, IL-6, and macrophage-inflammatory protein-1alpha than macrophages of TNF+/+LT+/+ animals did. In conclusion, endogenous TNF and/or LT contribute to host resistance to disseminated candidiasis, and their absence in TNF-/-LT-/- mice renders the animals susceptible through impaired recruitment of neutrophils and impaired phagocytosis of C. albicans.

Animals↗
PubMed1999

Soluble murine IL-1 receptor type I induces release of constitutive IL-1 alpha.

IL-1 alpha and IL-1 beta are proinflammatory cytokines involved in the pathogenesis of many infectious and noninfectious inflammatory diseases. To reduce IL-1 toxicity, extracellular domains of the soluble (s) IL-1R are shed from cell membranes and prevent triggering of cell-bound receptors. We investigated to what extent murine sIL-1RI can neutralize the IL-1 produced by LPS-stimulated macrophages. When mouse peritoneal macrophages were incubated with LPS, addition of sIL-1RI significantly inhibited the bioactivity of IL-1. Stimulation of cells with sIL-1RI alone induced no bioactive IL-1. When immunoreactive cytokine concentrations were measured with specific radioimmunoassays, sIL-1RI alone appeared to induce a significant release of IL-1 alpha in a concentration-dependent manner. This effect was independent of new protein synthesis. The production of IL-1 beta or TNF-alpha was not influenced by sIL-1RI. There was no interference of sIL-1RI with the IL-1 alpha radioimmunoassay. In mice, an i.v. injection of sIL-RI alone induced a rapid release of IL-1 alpha, but not of TNF-alpha or IL-1 beta. Treatment of mice with sIL-1RI improved the survival during a lethal infection with Candida albicans. In conclusion, sIL-1RI induces a rapid release of IL-1 alpha from cells, as well as into the systemic circulation. Although this IL-1 alpha may be inactivated in circulation by the same sIL-1RI, this phenomenon probably has immunostimulatory effects at local levels where the sIL-1RI-induced IL-1 alpha acts in a paracrine or autocrine manner.

Animals↗
PubMed1999

Disease-specific ex vivo stimulation of whole blood for cytokine production: applications in the study of tuberculosis.

As a simple method for field studies to assess the cytokine-status of patients with tuberculosis (TB), the use of whole blood instead of isolated cells has advantages, especially since the risk of contamination is minimal. Therefore, cytokine production in whole blood cultures was determined using non-specific and disease-specific stimuli. Heparinized blood from healthy volunteers was either incubated in closed vacutainer tubes or in tissue culture wells after dilution in culture medium. Dose-response and kinetics were investigated for the production of TNFalpha, IL-1beta, IL-1ra, IL-10 and IFNgamma. Patients with TB and healthy individuals were examined for IFN-gamma production in whole blood. In the absence of a stimulus, the production of cytokines is negligible in whole blood cultures. LPS induces the production of TNFalpha, IL-1beta, IL-1ra and IL-10; PHA induces the production of IFNgamma and IL-10. Live BCG induces the production of proinflammatory cytokines, irrespective of tuberculin skin status. In contrast, PPD and MTB-culture filtrate induce production of IFNgamma in skin-test positive and not in skin-test negative healthy subjects. Five out of 13 patients with TB had a low antigen-specific IFNgamma production, suggestive of a minimal or absent specific T-cell response. For most purposes, cultures in closed vacutainer tubes are optimal. If one wishes to focus on T-cell cytokines or if only small volumes of blood are available, dilution of whole blood in culture medium before incubation in tissue culture wells may be preferable.

Blood Cell Count↗
PubMed1999

Lipoprotein (a) concentrations in patients with familial combined hyperlipidemia and hypertension.

BACKGROUND: Lipoprotein (a) (Lp(a)) is an independent risk factor for coronary heart disease (CHD), and its association with hyperlipidemia and/or hypertension greatly increases the risk of premature CHD. METHODS: The present study assessed plasma concentrations of Lp(a) in hyperlipidemic subjects from families with well-defined familial combined hyperlipidemia (FCH) (n = 262) and from patients with hypertension (n = 168), and to compare it with Lp(a) plasma levels in healthy volunteers (n = 371). Lp(a) concentrations were measured using a specific radioimmunoassay. RESULTS: The Lp(a) plasma concentrations were similar in FCH patients (median 204 mg/l, range 16-2163 mg/l) and in the control group (155, 16-1846 mg/l; P > 0.05). The Lp(a) levels in patients with hypertension (157, 10-1985 mg/l) did not differ from those of controls (P > 0.05). The Lp(a) concentrations were similar in patients with essential hypertension (EH) and normal lipid levels, and in hyperlipidemic EH patients. A tendency towards higher levels of Lp(a) was observed in patients with secondary hypertension due to renal artery stenosis (RAS) (n = 26, Lp(a) 232, 16-1110 mg/l), but this was not statistically significant. CONCLUSIONS: Plasma concentrations of Lp(a) are similar in patients with FCH, with EH, either normo- or hyperlipidemic, and with RAS, when compared with healthy controls. However, measuring the Lp(a) levels in patients with either hyperlipidemia or hypertension remains important for assessing the risk potential for severe atherosclerosis in these patients.

Aged↗
PubMed1999

Do only circulating pyrogenic cytokines act as mediators in the febrile response? A hypothesis.

The classical model of the pathogenesis of fever suggests that pyrogenic cytokines, produced by leucocytes in the bloodstream in response to exogenous pyrogens, represent the distal mediators of the febrile response. They are recognized at the level of the organum vasculosum of the lamina terminalis in the central nervous system, where they induce synthesis of prostaglandins representing the central mediators of the coordinated responses leading to fever. This classical model is challenged by studies showing inconsistencies between the febrile response and the cytokine pattern, as well as by data demonstrating paradoxical hyperfebrile reactions in knock-out mice lacking cytokines or cytokine receptors. Moreover, no measurable cytokine concentrations are to be found in a variety of specific patients groups with febrile conditions. There are recent data in the literature suggesting that alternative pathways may be involved in the induction of fever, ranging from the use of vagal fibres to transmit the signals leading to fever, to local production of cytokines at the level of the hypothalamus, or the use of membrane-bound cytokines as mediators. A multipathway mechanism for the induction of fever is suggested.

Animals↗
PubMed1999

Integrin mediated adhesion of mononuclear cells from patients with familial hypercholesterolemia.

BACKGROUND: Low-density lipoproteins (LDL) can induce the adhesion of monocytes to endothelial cells. Monocytes of patients with familial hypercholesterolemia (FH) are exposed to high concentrations of LDL, and it has been reported that adhesiveness of these cells in hypercholesterolemic patients is enhanced. We investigated whether LFA-1 or VLA-4 mediated adhesion is altered in FH patients and whether HMG-CoA reductase inhibitors influence this adhesion. PATIENTS AND METHODS: LFA-1 and VLA-4 mediated adhesion to ICAM-1 and VCAM-1 coated beads was investigated using freshly isolated monocytes and T-lymphocytes from patients with homozygous FH, heterozygous FH (before and after cholesterol lowering treatment), and from controls. In addition, the expression of beta1- and beta2-integrins on these cells was determined. RESULTS: Both LFA-1 and VLA-4 mediated adhesion and integrin expression of monocytes and CD3+ cells from patients with homozygous FH and heterozygous FH was similar to that of monocytes from a control population. Treatment with HMG-CoA reductase inhibitors did not affect the adherence to ICAM-1 or VCAM-1, and did not influence the expression of integrins. CONCLUSIONS: In contrast to studies by others, we demonstrated in the present study that the actual LFA-1 and VLA-4 mediated adhesion of T-lymphocytes and monocytes is not altered in patients with FH.

Adolescent↗
PubMed1999

Increased susceptibility to systemic candidiasis in interleukin-6 deficient mice.

Interleukin-6 (IL-6) is a multifunctional cytokine that regulates multiple aspects of the innate immune response. It has been recently shown that endogenous IL-6 is crucial for an efficient defence against severe infections with Gram-negative and Gram-positive bacteria. The aim of the present study was to investigate the role of endogenous IL-6 in the defence against infection with the yeast Candida albicans. During experimental candidemia, IL-6 deficient mice (IL-6-/-) had a decreased survival and an increased fungal load in their organs when compared with IL-6+/+ controls, despite increased plasma concentrations of tumour necrosis factor-alpha (TNF), interleukin-1 alpha (IL-1 alpha) and IL-1 beta, IL-6-/- mice were not able to mount an efficient neutrophil response during the infection. When mice were rendered neutropenic by cyclophosphamide, neutropenic IL-6-/- mice were equally susceptible to C. albicans when compared to neutropenic IL-6+/+ mice, implying that neutrophils mediate the beneficial effect of endogenous IL-6. In conclusion, IL-6-/- mice are more susceptible to disseminated candidiasis, and the effect of IL-6 is most likely mediated by neutrophils.

Animals↗
PubMed1999

Fas-FasL interactions modulate host defense against systemic Candida albicans infection.

Fas-FasL costimulation modulates the production of proinflammatory cytokines, and MRL/lpr mice, which lack a functional Fas molecule, produce more proinflammatory cytokines. This study found that Fas-FasL interactions are involved in host defense against lethal infection with Candida albicans. Macrophages of MRL/lpr mice produced significantly more tumor necrosis factor and interleukin-1 after stimulation with C. albicans than did control MRL+/+ macrophages. Mortality of Fas-deficient mice with disseminated candidiasis was significantly lower than control animals' because of decreased fungal load and inhibition of the formation of invasive hyphae in their organs. Increased recruitment of neutrophils at the infection site appeared to be responsible for these effects. In contrast, phagocytosis and killing of C. albicans by neutrophils of MRL/lpr and MRL+/+ mice was similar. Absence of Fas-FasL interactions leads to increased cytokine production after C. albicans stimulation, protecting mice against disseminated candidiasis.

Animals↗
PubMed1999

Infusion of lipoproteins into volunteers enhances the growth of Candida albicans.

Infusion of reconstituted high-density lipoproteins (rHDL) is being studied in clinical trials as an adjunctive therapy for gram-negative sepsis. Since no data are available on its possible effects in systemic candidiasis, we investigated the effect of rHDL infusion into volunteers on the growth of Candida albicans. C. albicans growth was 10- to 100-fold higher in the plasma of volunteers infused with 80 or 100 mg/kg rHDL than in plasma collected before infusion; administration of 60 mg/kg rHDL had marginal effects. In vitro, the isolated lipoprotein subfractions had a growth-promoting effect on C. albicans. These data suggest potential adverse effects of rHDL if infused into patients with systemic candidiasis. Thus, rHDL infusion into patients with sepsis caused by an unknown microorganism may be contraindicated.

Animals↗
PubMed1999

Modulation of neutrophil function in host defense against disseminated Candida albicans infection in mice.

Neutrophils (PMNs) constitute the main mechanism of host defense against acute invasive and disseminated candidiasis. Recent studies have demonstrated that tumor necrosis factor-alpha (TNFalpha), interleukin-6 (IL-6) and granulocyte colony-stimulating factor (G-CSF) play an important role in the recruitment of PMNs at the site of invasive Candida infection. In the absence of either TNFalpha or IL-6, the course of experimental disseminated candidiasis is more severe, due to defective PMN recruitment. Treatment of mice with recombinant G-CSF (rG-CSF) leads to a significantly reduced mortality during disseminated candidiasis. The outgrowth of Candida albicans from the organs of rG-CSF-treated mice is significantly decreased. Treatment with the combination of rG-CSF and fluconazole has an additive effect on the reduction of fungal load in the organs. In subacute or chronic disseminated Candida infection, rG-CSF is less effective, indicating that neutrophil recruitment and activation are crucial in acute, life-threatening candidiasis, whereas other host defense mechanisms control the outcome of less overwhelming invasive Candida infection.

Animals↗
PubMed1999

Apolipoprotein E knock-out mice are highly susceptible to endotoxemia and Klebsiella pneumoniae infection.

Lipoproteins are able to neutralize bacterial lipopolysaccharide (LPS) and thereby inhibit the proinflammatory cytokine response. In a previous study, we demonstrated that hypercholesterolemic low density lipoprotein receptor knock-out (LDLr-/-) mice are protected against lethal endotoxemia and gram-negative infection. In the present study we investigated the susceptibility of apolipoprotein E knock-out mice (apoE-/-) to LPS and to Klebsiella pneumoniae. These mice have increased plasma lipoprotein concentrations in the very low density lipoprotein (VLDL)-sized fraction. Despite 8 -fold higher plasma cholesterol levels compared to controls, and in contrast to LDLr-/- mice, apoE-/- mice were significantly more susceptible to endotoxemia and to K. pneumoniae infection. Circulating TNFalpha concentrations after intravenously injected LPS were 4 - to 5-fold higher in apoE-/- mice, whereas IL-1alpha, IL-1beta, and IL-6 did not differ. This TNF response was not due to an increased cytokine production capacity of cells from apoE-/- mice, as ex vivo cytokine production in response to LPS did not differ between apoE-/- and control mice. The LPS-neutralizing capacity of apoE-/- plasma was significantly less than that of controls. Most likely, the absence of apoE itself in the knock-out mice explains the failure to neutralize LPS, despite the very high cholesterol concentrations.

Animals↗
PubMed1998

Bacterial lipopolysaccharide binds and stimulates cytokine-producing cells before neutralization by endogenous lipoproteins can occur.

Lipoproteins are able to bind to lipopolysaccharide (LPS) and neutralize its deleterious effects. However, it is not clear why the LPS-binding capacity of circulating lipoproteins, which is 10- to 10 000-fold above the maximal LPS concentrations found in septic patients, is not sufficient to inhibit the effects of LPS during an infection, whereas infusion of exogenous lipoproteins has a potent inhibitory action. In this study, the kinetics of LPS-neutralization by VLDL, LDL, and HDL were investigated, at lipoprotein-to-LPS ratios found in severe Gram-negative sepsis. At least 4-8-h preincubation of LPS with either LDL or HDL were necessary to inhibit 50% of the LPS-induced TNF-alpha production by human peripheral blood mononuclear cells (PBMC), whereas after 24 h of preincubation LDL or HDL strongly inhibited the TNF-alpha synthesis (70-90%, P<0.01). VLDL was the least effective lipoprotein fraction. In contrast, FITC-LPS bound to PBMC much more rapidly, with 70% of the total binding after 30 min, and 90% after 1-h incubation. The increase of LDL or HDL concentrations up to 10-fold (as in experimental models of hyperlipoproteinaemia) was able not only to further decrease TNF-alpha production after long LPS-lipoproteins preincubation periods, but also to improve the kinetics of LPS neutralization. In conclusion, LPS binds and stimulates the mononuclear cells in circulation before neutralization by endogenous lipoproteins can occur. Additional increase in the lipoprotein-to-LPS molar ratio (e.g. by infusion of exogenous lipoproteins) accelerates the kinetics of LPS neutralization, and may be useful as adjunctive therapy in severe Gram-negative infections.

Dose-Response Relationship, Drug↗
PubMed1998

LPS-induced cytokine production and expression of LPS-receptors by peripheral blood mononuclear cells of patients with familial hypercholesterolemia and the effect of HMG-CoA reductase inhibitors.

Inflammatory processes play an important role in atherogenesis, and proinflammatory cytokines such as interleukin-1beta (IL-1beta), IL-6, and tumour necrosis factor alpha (TNFalpha) are thought to be mediators in this phenomenon. We have previously established that peritoneal macrophages of LDL-receptor knock-out mice, which are hypercholesterolemic and are prone to atherosclerosis, have an increased LPS-induced cytokine production capacity, ex vivo. The aim of the present study was to investigate whether the process leading to atherosclerosis in patients with familial hypercholesterolemia (FH) is associated with increased cytokine production capacity of peripheral blood mononuclear cells (PBMC) and/or increased expression of adhesion molecules on monocytes and lymphocytes. Furthermore, we assessed the effect of cholesterol lowering on the production capacity of PBMC, as these drugs are beneficial with regard to cardiovascular diseases. LPS-induced IL-1beta and TNFalpha production by PBMCs of 21 heterozygous FH patients appeared to be similar to the production by PBMCs of 21 healthy volunteers. In addition, expression of the LPS-receptors CD14 and beta2-integrins in nine patients and controls did not differ either. In a second series of experiments, HMG-CoA synthesis inhibitors were ineffective to change the LPS-induced production by PBMC of IL-1alpha, IL-1beta, IL-1 receptor antagonist (IL-1ra), IL-6, and TNFalpha. In conclusion, cytokine production capacity of blood cells or the expression of LPS-receptors on circulating PBMC do not deviate in subjects with FH and also do not change as a result of treatment with cholesterol synthesis inhibitors.

Animals↗
PubMed1998

LPS-induced cytokine production and expression of beta2-integrins and CD14 by peripheral blood mononuclear cells of patients with homozygous familial hypercholesterolemia.

It has been suggested that proinflammatory cytokines such as tumor necrosis factor-alpha (TNF) and interleukin-1beta (IL-1), as well as adhesion molecules such as beta2-integrins and CD14, play a role in the pathogenesis of atherosclerosis. Familial hypercholesterolemia (FH) is an autosomal disease in which defective or absent LDL receptors are the cause for extreme LDL concentrations and early development of atherosclerosis. We studied lipopolysaccharide-induced cytokine production and the expression of adhesion molecules by mononuclear cells of three homozygous FH patients and compared them with first-degree relatives and healthy controls. There was a tendency towards increased cytokine production by cells of FH patients, whereas the expression of adhesion molecules was not modified compared to controls. In addition, LDL-apheresis inhibited IL-1 and TNF production and the expression of CD11a, CD11b, CD11c and CD14 by the mononuclear cells of FH patients and this may be an additional beneficial effect of LDL-apheresis apart of decreasing LDL concentrations.

Adolescent↗
PubMed1998

The effect of renin-angiotensin system inhibitors on pro- and anti-inflammatory cytokine production.

The balance between pro- and anti-inflammatory cytokines has been implicated in the pathogenesis of infectious and auto-immune diseases, and its modulation has been proposed as a potential therapeutic target. The results reported in the present study show that modulators of the renin-angiotensin system, such as the angiotensin-converting enzyme (ACE)-inhibitor captopril and the angiotensin II receptor type I antagonist valsartan, have potent inhibitory effects on the lipopolysaccharide (LPS)-stimulated production of pro-inflammatory cytokines tumour necrosis factor (TNF) and interleukin-1 (IL-1) in vitro. The anti-inflammatory cytokine IL-1Ra is increased by captopril, whereas IL-6 production is decreased by valsartan. These effects are exerted mainly at high concentrations of the drugs. Administration of one dose of captopril or valsartan in therapeutic dosages to patients with essential hypertension did not influence LPS-stimulated production of cytokines by whole blood. In conclusion, despite inhibitory effects on pro-inflammatory cytokine production in vitro, it is unlikely that captopril or valsartan could be used in anticytokine therapeutic strategies in vivo.

Angiotensin II↗