Modulation of in vitro monocyte cytokine responses to Leishmania donovani. Interferon-gamma prevents parasite-induced inhibition of interleukin 1 production and primes monocytes to respond to Leishmania by producing both tumor necrosis factor-alpha and interleukin 1.

Reiner, Neil E.; Ng, Wei Lin; Wilson, Carla; McMaster, W. Robert; Burchett, Sandra

doi:10.1172/jci114654

Cited by 100 publications

(61 citation statements)

References 51 publications

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“…Amastigotes of either the Sudan (2S) or the Ethiopian (LV9) strains of L. donovani were isolated as described (2).…”

Section: Methodsmentioning

confidence: 99%

“…Sources of RPMI 1640 medium, Hanks' balanced salt solution (HBSS), Histopaque, and fixed Staphylococcus aureus cells were as described (2 (2 ,qg/ml), soybean trypsin inhibitor (20 pug/ml), 2-mercaptoethanol (0.036%, vol/vol), and Nonidet P-40 (0.1%, vol/vol) were scraped and transferred into microcentrifuge tubes and extracted by sonication (30 W) for 15 s at 0C with a Branson sonifier. Extracts were centrifuged (60 s at 1000 x g), and the supernatants were added to 9 vol of acetone and kept at -20'C for 2 hr.…”

Section: Methodsmentioning

confidence: 99%

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Defective stimulus-response coupling in human monocytes infected with Leishmania donovani is associated with altered activation and translocation of protein kinase C.

Olivier

Brownsey

Reiner

1992

Proc. Natl. Acad. Sci. U.S.A.

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120

103

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Stimulus-response coupling through protein kinase C (PKC) was shown to be defective in mononuclear phagocytes (MO) infected with Leishmania donovani. Phorbol 12-myristate 13-acetate (PMA)-induced oxidative burst activity and protein phosphorylation were markedly attenuated in infected M+. These results were not explained either by quantitative alterations in amounts of PKC or by altered phorbol ester binding but were related to defects in kinase activation. Analysis in vitro of the kinetic properties of PKC from infected MO revealed an -2-fold increase in the concentration of 1,2-dioleoyl-rac-glycerol required to achieve halfmaximal kinase activation. Evidence for abnormal PKC activation in vivo was reflected by attenuation of PMA-induced translocation of enzyme to the particulate fraction of infected cells. These results provide direct evidence that infection with Leishmania inhibits activation of, and therefore intracellular signaling dependent on, PKC. Inhibition of stimulus-response coupling through PKC provides a basis for understanding impairment of cellular activation by Leishmania and may contribute to chronic infection.Numerous intracellular pathogens including Leishmania (1-3), Yersinia (4), human immunodeficiency virus 1 (5, 6), and others promote mononuclear phagocyte (MO) dysfunction and this may contribute to chronic infection. For example, infection of MO with Leishmania donovani results in defective responses to -y-interferon for the expression of major histocompatibility complex class II genes (1) as well as to decreased responsiveness both to lipopolysaccharide for the induction of interleukin 1 production (2) and to phorbol esters for the induction of c-fqs gene expression (3) and the oxidative burst (7). These MO responses to extracellular stimuli may require activation of protein kinase C (PKC) (8, 9), and this suggests that defective stimulus-response coupling in MO infected with Leishmania may be brought about by altered activation of PKC. To examine this possibility, PKCdependent cell signaling was studied in MO infected with L. Mops (25 mM), EGTA (2 mM), EDTA (5 mM), P-glycerophosphate (50 mM), benzamidine (2.5 mM), leupeptin (2 kug/ml), phenylmethylsulfonyl fluoride (0.2 mM), pepstatin (2 ,qg/ml), soybean trypsin inhibitor (20 pug/ml), 2-mercaptoethanol (0.036%, vol/vol), and Nonidet P-40 (0.1%, vol/vol) were scraped and transferred into microcentrifuge tubes and extracted by sonication (30 W) for 15 s at 0C with a Branson sonifier. Extracts were centrifuged (60 s at 1000 x g), and the supernatants were added to 9 vol of acetone and kept at -20'C for 2 hr. Protein precipitates were collected by centrifugation (10 min at 12,000 x g), dried, and subjected to two-dimensional SDS/PAGE based on the method of O'Farrell (12). Protein samples were digested (20 min at 200C) in buffer (pH 9.5) containing urea (9 M), Nonidet P-40 (1%; vol/vol), ampholytes (20 pul/ml, pH 5-8), 2-mercaptoethanol (5%; vol/vol), and the same phosphatase and proteinase

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“…Amastigotes of either the Sudan (2S) or the Ethiopian (LV9) strains of L. donovani were isolated as described (2).…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Defective stimulus-response coupling in human monocytes infected with Leishmania donovani is associated with altered activation and translocation of protein kinase C.

Olivier

Brownsey

Reiner

1992

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

120

103

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“…Leishmania infection does not induce TNF-α or IL-12 production in human monocytes (Reiner et al 1990, Ghalib et al 1995, Sartori et al 1997 or macrophages but inhibits IL-12 production by LPS-stimulated monocytes. In addition, we have shown (de Almeida et al 2003) that some striking inhibitory effects, as for CD54 expression or IL-12, were only observed if the infected cells were challenged with an inflammatory stimulus, LPS.…”

Section: Parasite's General Strategy At the Initial Phases Of Leishmamentioning

confidence: 98%

Leishmanial infection: analysis of its first steps. A review

Almeida

Vilhena²,

Barral

et al. 2003

Mem. Inst. Oswaldo Cruz

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“…In previous experiments, we have shown that rR-IFN-y pretreatment of 3-d-old rats dramatically improved survival and splenic content of bacteria among L. monocytogenes-inoculated animals (1 1). Because rR-IFN-y treatment may alter TNF-(U production (9,19,20) and cellular response to TNF-a (20-24), we camed out a series of experiments using rR-IFN-y at a concentration that we predicted would be, by itself, suboptimal for animal protection. Splenic content of TNF in bacteria-challenged 3-d-old rats was not increased for rR-IFN-y-pretreated animals ( Table 2).…”

Section: Resultsmentioning

confidence: 99%

Role of Tumor Necrosis Factor-α and Interferon-γ in Newborn Host Defense against Listeria Monocytogenes Infection

1992

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Dc~purtmc~nr c!/'Pc.diutric:~, Dullro~r.sic~ UnivcJr.sit~: /luli/u.\-, Novu Scoria. Chnudu ABSTRACI'. The fetus and newborn are particularly susceptible to Listeria monocytogenes infection. We used a newborn rat animal model to investigate neonatal host defense against Listeria. In this animal model, newborn (3-d-old) rats are more susceptible to L. monocytogenes than older animals. Juvenile (23-d-old) L. monocytogenesinfected rats pretreated with lipopolysaccharide (LPS) had a lower bacterial load in blood than control animals, whereas LPS pretreated newborn rats had a higher bacterial load. Because LPS is a potent inducer of tumor necrosis factor (TNF) and TNF enhances host defense against this organism in adult animals, we assessed TNF content in splenic homogenates for animals of different ages. The age at which TNF was detectable in L. monocytogenes-Infected rats corresponded to the age at which LPS became active in preventing severe bacteremia. TNF was less than 1 unit/ mL in splenic homogenates taken from rats less than 8 d of age, whereas 16-d-old rats infected with L. monocytogenes 1 d earlier had greater than 80 units/mL ( p e 0.0001 for 3-d-old versus 16-d-old rats). We also assessed the responsiveness of rats to exogenous TNF-a. Juvenile rats pretreated with TNF-a before L. monocytogenes infection had decreased bacterial load in spleen ( p e 0.02 versus controls) and better survival at 7 d ( p e 0.05 versus controls), whereas newborn rats did not improve with TNFa pretreatment ( p > 0.05 treated versus controls for splenic bacterial load and 7-d survival). However, when newborn rats were pretreated with both interferon-y (IFN-y) and TNF-a, splenic bacterial content was decreased compared to animals pretreated with PBS, IFN-y, or TNF-a alone ( p < 0.005 combination versus TNF-a, IFN-y, or PBS).Similarly, survival also was improved for newborn rats pretreated with both IFN-y and TNF-a compared to controls pretreated with either of these agents alone ( p < 0.02 combination versus control, p > 0.05 TNF-a or IFN-y versus controls). We conclude that TNF production is decreased among newborn rats challenged with L. monocytogenes compared to TNF production in older animals. TNF-a does not enhance resistance of newborn rats to L. monocytogenes unless they are pretreated with IFN-y as well. (Pediatr Res 32: 460-464, 1992) Abbreviations TNF, tumor necrosis factor IFN, interferon rR-IFN-y, recombinant rat interferon-y LPS, lipopolysaccharide

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Modulation of in vitro monocyte cytokine responses to Leishmania donovani. Interferon-gamma prevents parasite-induced inhibition of interleukin 1 production and primes monocytes to respond to Leishmania by producing both tumor necrosis factor-alpha and interleukin 1.

Abstract: Cytokines produced by mononuclear cells are important regulatory and effector molecules and evidence has been presented to support a role at least for tumor necrosis factor-a (TNF-a) and interferon-y (IFN-y) in host defense against Leishmania.

Cited by 100 publications

References 51 publications

Defective stimulus-response coupling in human monocytes infected with Leishmania donovani is associated with altered activation and translocation of protein kinase C.

Defective stimulus-response coupling in human monocytes infected with Leishmania donovani is associated with altered activation and translocation of protein kinase C.

Leishmanial infection: analysis of its first steps. A review

Role of Tumor Necrosis Factor-α and Interferon-γ in Newborn Host Defense against Listeria Monocytogenes Infection

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