Pharmacologic Inhibitors of Tumor Necrosis Factor Production Exert Differential Effects in Lethal Endotoxemia and in Infection with Live Microorganisms in Mice

Netea, Mihai G.; Blok, W.L.; Kullberg, Bart‐Jan; Bemelmans, M. H. A.; Vogels, M.T.E.; Buurman, Wim A.; Meer, J.W.M. van der

doi:10.1093/infdis/171.2.393

Cited by 66 publications

(40 citation statements)

References 37 publications

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“…Similar findings have also been reported after thalidomide pretreatment in an experimental model of meningitis caused by Mycobacterium bovis, in which thalidomide not only reduced TNF-␣ levels and white blood cell counts in plasma and cerebrospinal fluid, but it also ameliorated the clinical score for meningitis (21,22). In contrast to the results of the present study, oral administration of thalidomide in a model of thigh infection caused by Klebsiella pneumoniae in mice did not have any influence on the serum cytokine levels measured (16). However, in that study, blood sampling was performed 24 h after bacterial inoculation; thalidomide might have an effect on the early secretion of TNF-␣ that leads to sepsis, as shown in the present study (Fig.…”

Section: Discussioncontrasting

confidence: 64%

Effective Immunomodulatory Treatment ofEscherichia coliExperimental Sepsis with Thalidomide

Giamarellos‐Bourboulis

Poulaki

Kostomitsopoulos

et al. 2003

Antimicrob Agents Chemother

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Thalidomide, an agent which inhibits biosynthesis of tumor necrosis factor alpha (TNF-␣) and which is used to treat a variety of chronic inflammatory conditions, was investigated as therapy for experimental sepsis. Sepsis was induced by intraperitoneal injection of 10 7 CFU of Escherichia coli per kg of body weight to 80 Wistar rats divided into four groups. Group A consisted of 24 control animals that did not receive any pretreatment, group B consisted of 18 vehicle-treated control animals pretreated with seed oil, group C consisted of 30 rats administered thalidomide diluted in seed oil at a dose of 50 mg/kg 30 min before bacterial challenge, and group D consisted of eight animals that were not challenged with E. coli but that were used for white blood cell count determination. Sepsis was determined by measurement of vital signs before and 6 h after bacterial challenge. After 6 h the animals were killed and blood was sampled for culture; white blood cell count determination; and determination of endotoxin (lipopolysaccharide), TNF-␣, interleukin-1␤ (IL-1␤), and IL-6 levels. The levels of these cytokines were also estimated in the supernatants of human monocytes pretreated with thalidomide after exposure to the isolate. Sepsis developed in all vehicle-treated control animals and controls by 6 h after bacterial challenge but in only 10 animals (33.3%) pretreated with thalidomide (P < 0.0001). Six hours after bacterial challenge all animals had similar levels of endotoxemia, IL-1␤, and IL-6. The mean white blood cell count for groups A, B, and C were 5,631.1, 2,638.9, and 8,169.3 cells/l, respectively (P value between groups, <0.0001); the TNF-␣ levels were 77.3, 107.2, and 26.1 pg/ml, respectively (P values between groups, <0.0001). Pretreatment of human monocytes with thalidomide prevented the secretion of TNF-␣ and IL-1␤ but not that of IL-6. It is concluded that thalidomide exerts a considerable anti-inflammatory effect by preventing evolution to sepsis and by decreasing the level of production of TNF-␣ and therefore deserves to be further evaluated in research for the therapy of sepsis.Over the last decade the idea of inhibiting tumor necrosis factor alpha (TNF-␣) biosynthesis or TNF-␣ activity as an immunomodulatory therapy for sepsis caused by gram-negative organisms has been thoroughly explored with various animals and in clinical trials (4, 18). Results from recent human studies with the p55 tumor necrosis factor receptor protein (lenercept), however, were disappointing (1). Thalidomide is an old agent that in 1998 was approved for use by the Food and Drug Administration for the treatment of erythema nodosum leprosum. Since then, further knowledge on its immunomodulatory properties has been acquired. A major effect of this drug is reduction of the half-life of TNF-␣ mRNA in human monocytes (7). Thalidomide is used to treat a variety of dermatological conditions, such as cutaneous lupus erythematosus and Behçet's syndrome; various conditions associated with human immunodeficiency virus infection like apht...

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Section: Discussioncontrasting

confidence: 64%

Effective Immunomodulatory Treatment ofEscherichia coliExperimental Sepsis with Thalidomide

Giamarellos‐Bourboulis

Poulaki

Kostomitsopoulos

et al. 2003

Antimicrob Agents Chemother

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“…To assess whether the same protection is obtained in a more sustained model of infection, K. pneumoniae 10 6 CFU/mouse was injected intramuscularly (i.m.) (LD 50 5 ϫ 10 5 CFU/C57Bl/6J mouse) into the left thigh muscle of the animals as described (23). Survival was assessed daily for 14 d, in groups of at least 18 (i.v.…”

Section: Methodsmentioning

confidence: 99%

Low-density lipoprotein receptor-deficient mice are protected against lethal endotoxemia and severe gram-negative infections.

Netea

Demacker²,

Kullberg³

et al. 1996

J. Clin. Invest.

193

124

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Lipoproteins can bind lipopolysaccharide (LPS) and decrease the LPS-stimulated production of pro-inflammatory cytokines. We investigated the effect of increased plasma concentrations of low-density-lipoproteins (LDL) on survival and cytokine production after a lethal challenge with either LPS or live Gram-negative bacteria in LDL receptor deficient mice (LDLR Ϫ / Ϫ ). The LDLR Ϫ / Ϫ mice challenged with LPS had an eightfold increased LD 50 when compared with the wild type controls (C57Bl/6J), while tumor necrosis factor ␣ (TNF ␣ ) and interleukin-1 ␣ (IL-1 ␣ ) plasma concentrations were decreased twofold. LDLR Ϫ / Ϫ mice had significantly lower and delayed mortality than control mice after infection with Klebsiella pneumoniae. No differences in the outgrowth of bacteria in the organs were present between the two groups, while circulating cytokine concentrations were decreased twofold in LDLR Ϫ / Ϫ mice. In contrast, the LPS-stimulated in vitro production of cytokines by peritoneal macrophages of LDLR Ϫ / Ϫ mice was significantly increased compared with controls. This increase was associated with enhanced specific binding of LPS to the macrophages of LDLR Ϫ / Ϫ mice. In conclusion, endogenous LDL can protect against the lethal effects of endotoxin and Gram-negative infection. At least part of this protection is achieved through decreased in vivo production of pro-inflammatory cytokines, in spite of increased cytokine production capacity. ( J. Clin. Invest. 1996. 97:1366-1372). Key words: lipopolysaccharide • gram-negative infection • tumor necrosis factor • interleukin-1 • low-density lipoproteins.

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“…IC 50 of chlorpromazine and tri£uoperazine was found to be 0.248 mg ml 31 and 0.192 mg ml 31 , respectively, against C. albicans (Fig. 1).…”

Section: Resultsmentioning

confidence: 93%

“…3 H-thymidine (speci¢c activity 1800 mCi mmol 31 ), 14 ). For experimental purposes, the organism was grown in mineral salt solution [17] as shake cultures at 37³C.…”

Section: Methodsmentioning

confidence: 99%

“…Exponentially growing cells (9 h growth) were centrifuged at 10 000Ug for 10 min and suspended in fresh media at a density of 6U10 6 cells ml 31 containing K-factor (1 Wg ml 31 ) and incubated at 37³C for 3 h. Cell synchrony was checked by analyzing the aliquots at di¡erent time intervals by £ow cytometry. After 3 h only V30% of the cells were found to be in S phase while the rest were arrested at the G 1 /S interphase (data not shown).…”

Section: Cell Synchronizationmentioning

confidence: 99%

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Cell cycle effects of the phenothiazines: trifluoperazine and chlorpromazine in Candida albicans

Sharma¹

2001

FEMS Microbiology Letters

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The study demonstrates the in vitro effectiveness of phenothiazine compounds, i.e. chlorpromazine and trifluoperazine against Candida albicans. Anticandidal effect of these drugs is suggested to be because of their interaction with Ca 2 /calmodulin dependent protein phosphorylation.3 H-thymidine uptake studies revealed that both these compounds affect the DNA synthesis along with decrease in activities of nuclear calmodulin (CaM) and Ca 2 /calmodulin dependent protein kinase (CaMPK). Failure in cell growth was due to defect in CaM mediated cell cycle arrest. Flow cytometric analysis showed that progression through G 1 and mitotic phase was affected when cells after K-factor arrest were grown in the presence of chlorpromazine or trifluoperazine. These drugs also produced significant decline in the cellular lipids and phospholipids. 14 C-acetate incorporation studies further substantiated these results. We suggest that chlorpromazine or trifluoperazine affect the cell cycle through DNA synthesis (S phase) and cell division phases which are governed by calmodulin and Ca 2 / calmodulin dependent protein phosphorylation and lipids and phospholipids appear to be additional targets of phenothiazine compounds in C. albicans. These results will have important significance in the development of new anticandidal compounds. ß

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Pharmacologic Inhibitors of Tumor Necrosis Factor Production Exert Differential Effects in Lethal Endotoxemia and in Infection with Live Microorganisms in Mice

Cited by 66 publications

References 37 publications

Effective Immunomodulatory Treatment ofEscherichia coliExperimental Sepsis with Thalidomide

Effective Immunomodulatory Treatment ofEscherichia coliExperimental Sepsis with Thalidomide

Low-density lipoprotein receptor-deficient mice are protected against lethal endotoxemia and severe gram-negative infections.

Cell cycle effects of the phenothiazines: trifluoperazine and chlorpromazine in Candida albicans

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