[leish-l] Articles found by RefScout 2005/02/25 newsletter 8/2005 Part II

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PMID: 15490320
 

TITLE: Gene expression profiles of inducible nitric oxide synthase and
cytokines
in Leishmania major-infected macrophage-like RAW 264.7 cells treated with
gallic
acid.

AUTHORS: Oliver A Radtke, Albrecht F Kiderlen, Oliver Kayser, Herbert Kolodziej

AFFILIATION: Institut für Pharmazeutische Biologie, Freie Universität Berlin,
Berlin, Germany.

REFERENCE: Planta Med 2004 Oct 70(10):924-8

The effects of gallic acid on the gene expressions of inducible nitric 
oxide synthase (iNOS) and the cytokines interleukin (IL)-1, IL-10, IL-12
, IL-18, TNF-alpha, and interferon (IFN)-gamma were investigated by 
reverse-transcription polymerase chain reaction (RT-PCR). The 
experiments were performed in parallel in non-infected and in L. major-
infected RAW 264.7 cells and the expression profiles were compared with 
those mediated by IFN-gamma plus lipopolysaccharide (LPS). The infection
 per se induced the expression first of IL-1 and TNF-alpha mRNA, later 
that of IL-10 mRNA. Gallic acid induced low and transient levels of TNF-
alpha and IL-10 in non-infected cells, and it clearly enhanced and 
prolonged iNOS and cytokine mRNA expressions in Leishmania-parasitised 
cells. Interestingly, and in contrast to activation by IFN-gamma/LPS, 
gallic acid also stimulated Leishmania-infected cells to produce IFN-
gamma mRNA. For IFN-alpha, a sandwich immunoassay was performed to 
determine its amount present in the supernatant of gallic acid-
stimulated RAW 264.7 cells. In showing predominant stimulation of 
infected cells and the induction especially of IFN-gamma, a cytokine 
that plays a central role in antimicrobial macrophage and T cell 
regulation, these data provide the basis for an immunological concept of
 gallic acid and possibly other plant polyphenols for their beneficial 
effects in various infectious conditions.




PMID: 12960263
 

TITLE: Multinutrient undernutrition dysregulates the resident macrophage
proinflammatory cytokine network, nuclear factor-kappaB activation, and nitric
oxide production.

AUTHORS: Gregory M Anstead, Bysani Chandrasekar, Qiong Zhang, Peter C Melby

AFFILIATION: Medical Service, Department of Veterans Affairs Medical Center,
South Texas Veterans Health Care System, San Antonio, TX, USA.
anstead at uthscsa.edu

REFERENCE: J Leukoc Biol 2003 Dec 74(6):982-91

We have described previously a murine model of multinutrient 
undernutrition that reproduced the features of moderate human 
malnutrition and led to increased early dissemination of Leishmania 
donovani. Peritoneal cells from these malnourished mice produced 
decreased NO after stimulation with IFN-gamma/LPS. We hypothesized that 
malnutrition may cause a deficit in NF-kappaB activation, a principal 
transcription pathway for inducible NO synthase and proinflammatory 
cytokines. Macrophages from malnourished mice, stimulated with IFN-gamma
/LPS, showed increased IL-6 production and decreased IL-10 and TNF-alpha
 production. Neutralization of TNF-alpha in macrophage cultures from the
 control mice mimicked the effect of malnutrition on NO and IL-10 
production, whereas supplemental TNF-alpha added to cultures of 
macrophages from malnourished mice increased NO secretion. NF-kappaB 
nuclear binding activity in macrophages from the malnourished mice was 
reduced early after stimulation, but increased to supranormal values by 
16- or 24-h poststimulation. Blocking NO production in the macrophages 
from the control mice reproduced the effect of malnutrition on the late 
activation of NF-kappaB, whereas supplemental NO decreased the late NF-
kappaB activation in the malnourished mice. Thus, in macrophages from 
the malnourished mice, initial deficits in NF-kappaB activity probably 
lead to decreased TNF-alpha, which results in decreased NO; however, IL-
6 is regulated independently from NF-kappaB and TNF-alpha. The late 
activation of NF-kappaB in the macrophages from malnourished mice is due
 to absence of negative feedback from NO.




PMID: 12871028
 

TITLE: Evidences for iNOS expression and nitric oxide production in the human
macrophages.

AUTHORS: M A Panaro, O Brandonisio, A Acquafredda, M Sisto, V Mitolo

AFFILIATION: Department of Human Anatomy and Histology, Immunology and
Infectious Diseases, University of Bari, Bari, Italy.
ma.panaro at anatomia.uniba.it

REFERENCE: Curr Drug Targets Immune Endocr Metabol Disord 2003 Sep 3(3):210-21

Nitric oxide (NO) is a pleiotropic mediator of numerous biological 
processes, including smooth muscle relaxation, neurotransmission and 
defence against pathogens. In addition, NO is involved in the 
pathogenesis and control of inflammation, tumors, autoimmunity, and 
infectious and chronic degenerative diseases. NO, a highly reactive 
radical, is produced from L-arginine and oxygen by the enzyme NO 
synthase (NOS). Three NOS isoforms have been identified: two distinct 
NOS isoforms are constitutively expressed in cells, whereas a third 
isoform, inducible NOS (iNOS), is transcribed in response to specific 
stimuli. In particular, iNOS is responsible for the discontinuous 
synthesis of high amounts of NO and was originally characterized in 
murine macrophages after exposure to cytokines and/or microbial products
. A wide range of microorganisms is sensibly inhibited in its 
development by NO, like fungi, bacteria, protozoa and viruses. Although 
NO production and its antimicrobial effect appear well established in 
rodent macrophages, the existence of L-arginine pathway in human 
mononuclear phagocytes has long been disputed. Recently, evidences 
showing the iNOS activity and NO production in other animal models, 
including humans, are now emerging, even if the NO induction has been 
more difficult to demonstrate. The present observations provide evidence
 for the occurrence of iNOS protein expression and NO production in 
human macrophages cultured in vitro.




PMID: 12065498
 

TITLE: Identification of a disulfide isomerase protein of Leishmania major as a
putative virulence factor.

AUTHORS: Y Ben Achour, M Chenik, H Louzir, K Dellagi

AFFILIATION: Laboratoire d'Immunologie (LAF301), Institut Pasteur de Tunis,
1002
Tunis-Belvédère, Tunisia.

REFERENCE: Infect Immun 2002 Jul 70(7):3576-85

Several approaches have been previously used to elucidate the genetic 
basis of Leishmania virulence. In general, they were based on laboratory
 Leishmania clones genetically modified or grown in the presence of 
selecting agents. In a previous study, we demonstrated that Leishmania 
major freshly isolated from human cutaneous lesions showed significant 
differences in the severity of the experimental disease induced in BALB/
c mice. Here, using the mRNA differential display technique, we analyzed
 gene expression in L. major promastigotes showing different levels of 
virulence. We have identified a novel Leishmania gene encoding a 477-
amino-acid protein exhibiting two distinct regions that are identical to
 the putative active-site sequence (CGHC) of the eukaryotic protein 
disulfide isomerase (PDI). The recombinant protein displayed a specific 
PDI enzymatic activity. This L. major disulfide isomerase protein (LmPDI
) is predominantly expressed, at both the mRNA and protein levels, in 
highly virulent strains. Specific PDI inhibitors abolished the enzymatic
 activity of the recombinant protein and profoundly affected parasite 
growth. These findings suggest that LmPDI may play an important role in 
Leishmania natural pathogenicity and may constitute a new target for 
anti-Leishmania chemotherapy.




PMID: 12085314
 

TITLE: Chemokine-induced leishmanicidal activity in murine macrophages via the
generation of nitric oxide.

AUTHORS: Sandip Bhattacharyya, Sanjukta Ghosh, Biplab Dasgupta, Debashis
Mazumder, Syamal Roy, Subrata Majumdar

AFFILIATION: Department of Microbiology, Bose Institute, Calcutta 700 054,
India. sandip39 at hotmail.com

REFERENCE: J Infect Dis 2002 Jun 185(12):1704-8

This study explored the role of the proinflammatory chemokines 
macrophage inflammatory protein (MIP)-1alpha and macrophage 
chemoattractant protein (MCP)-1 for development of antileishmanial 
activity. There was substantial inhibition in nitrite generation in 
Leishmania donovani-infected macrophages. A marked elevation of nitrite 
generation and induction of inducible nitric oxide (NO) synthase (iNOS) 
mRNA was found in chemokine-primed parasite-infected macrophages. Tumor 
necrosis factor-alpha, which is the priming signal for NO production, 
was also up-regulated under similar experimental conditions. The priming
 with chemokine inhibited the multiplication of L. donovani amastigotes 
within the intramacrophageal milieu. The antileishmanial effect of 
chemokines was almost completely abrogated when the macrophages were 
preincubated with l-N-monomethyl arginine, the specific inhibitor of 
iNOS. The results of this investigation suggest that the CC chemokines 
MIP-1alpha and MCP-1 orchestrate an antileishmanial armamentarium via 
the induction of an NO-mediated regulatory mechanism to control the 
intracellular growth and multiplication of the Leishmania protozoan.








PMID: 11745019
 

TITLE: Antileishmanial activity of hydrolyzable tannins and their modulatory
effects on nitric oxide and tumour necrosis factor-alpha release in macrophages
in vitro.

AUTHORS: H Kolodziej, O Kayser, A F Kiderlen, H Ito, T Hatano, T Yoshida, L Y
Foo

AFFILIATION: Institut für Pharmazie, Pharmazeutische Biologie, Freie
Universität Berlin, Berlin, Germany. kolpharm at zedat-fu-berlin.de

REFERENCE: Planta Med 2001 Dec 67(9):825-32

A series of 27 hydrolyzable tannins and related compounds was tested for
 antiparasitic effects against both extracellular promastigote and 
intracellular amastigote Leishmania donovani organisms. In parallel, the
 compounds were evaluated for their immunomodulatory effects on 
macrophage functions, including release of nitric oxide (NO), tumour 
necrosis factor-alpha (TNF-alpha) and interferon (IFN)-like properties 
using several functional assays. Of the series of polyphenols tested, 
only gallic acid (54 microM NO) and its methyl ester (32 microM NO) 
induced murine macrophage-like RAW 264.7 cells to release NO in 
appreciable amounts (IFN-gamma/LPS 119 microM NO). The in vitro TNF-
inducing potential of the polyphenols examined increased in the order of
 oligomeric ellagitannins (EC(50) > 25 microg/ml) < monomeric 
ellagitannins, gallotannins (EC(50) 8.5 to > 25 microg/ml) < C-
glucosidic ellagitannins, dehydroellagitannins (EC(50) 0.6 - 2.8 microg/
ml) at the host cell subtoxic concentration of 50 microg/ml. Furthermore
, promastigotes of Leishmania donovani were assayed in the presence of 
these polyphenols and the results showed that none of the compounds was 
significantly toxic (EC(50) > 25 microg/ml) to the extracellular forms. 
In contrast, all polyphenols showed pronounced antileishmanial 
activities (EC(50) < 0.4 - 12.5 versus 7.9 microg/ml for Pentostam) 
against intracellular amastigotes of L. donovani residing within RAW 
cells. Noteworthy, most compounds exhibited low cytotoxicity against the
 murine host cells (EC(50) >25 microg/ml). Furthermore, some 
ellagitannins and the majority of dehydroellagitannins induced potent 
interferon-like activities as reflected by inhibition of the cytopathic 
effect of encephalomyocarditis virus on fibroblast L929 cells. This is 
the first report on hydrolyzable tannins as a new class of natural 
products with leishmanicidal activity including their potential for 
inducing the release of NO, TNF and IFN-like activity in macrophage-like
 RAW cells.




PMID: 11558561
 

TITLE: Proanthocyanidins and related compounds: antileishmanial activity and
modulatory effects on nitric oxide and tumor necrosis factor-alpha-release in
the murine macrophage-like cell line RAW 264.7.

AUTHORS: H Kolodziej, O Kayser, A F Kiderlen, H Ito, T Hatano, T Yoshida, L Y
Foo

AFFILIATION: Institute of Pharmacy, Pharmaceutical Biology, Freie Universität
Berlin, Germany.

REFERENCE: Biol Pharm Bull 2001 Sep 24(9):1016-21

A series of 17 proanthocyanidins and structurally related compounds was 
tested for activity against Leishmania donovani amastigotes and 
promastigotes in vitro. Most of the polyphenols significantly inhibited 
the intracellular survival of L. donovani amastigotes (EC50 0.8-10.6 nM
) when compared with the antileishmanial drug Pentostam (EC50 10.6 nM), 
but all were inactive against the extracellular form (EC50 7.8 to >86 nM
). Noteworthy is that all compounds exhibited only moderate or no 
cytotoxicity against the murine host cells (EC50 7.8 to >56 nM; >25 
microg/ml). These polyphenols were further evaluated for 
immunomodulatory effects on macrophage functions, including release of 
nitric oxide (NO), tumor necrosis factor-alpha (TNF) and interferon (IFN
)-like properties using several functional assays. The results showed 
that all compounds induced murine RAW 264.7 cells only moderately to 
release NO (7-26 microM) relative to the reference stimulus IFN-gamma/
LPS (119 microM). The TNF-inducing potential of the polyphenols 
producing 50% lysis in murine L929 cells ranged from absent to 138 U/ml 
at the host cell subtoxic concentration of 50 microg/ml. The highest TNF
-inducing activity was associated with those flavan-3-ols with galloyl 
groups (98-127 U/ml). For proanthocyanidins, it appeared that an 
increase in the flavanyl chain length did not enhance the induction of 
TNF-release (32-86 U/ml and below detection limits for oligomers and 
polymers, respectively). With interferon-like activities, phylloflavan 
and a prodelphinidin polymer showed appreciable cytoprotective effects, 
as reflected by the inhibition of the cytopathic effect of 
encephalomyocarditis virus on L929 fibroblast cells (38 and 36 U/ml, 
respectively). All remaining compounds displayed only negligible or 
moderate protective effects at subtoxic concentrations up to 25 microg/
ml (<5 to 12 U/ml). These results indicate that proanthocyanidins and
 related compounds have favorable antileishmanial activity in vitro and 
might be considered as beneficial immunological response modifiers 
provided there are no bioavailability problems.




PMID: 11437830
 

TITLE: Leishmania donovani lipophosphoglycan causes periphagosomal actin
accumulation: correlation with impaired translocation of PKCalpha and defective
phagosome maturation.

AUTHORS: Holm A, K Tejle, K E Magnusson, A Descoteaux, B Rasmusson

AFFILIATION: Division of Medical Microbiology, Department of Health and
Environment, Faculty of Health Sciences, Linköping University, S-581 85
Linköping, Sweden. asaholm at hem.passagen.se

REFERENCE: Cell Microbiol 2001 Jul 3(7):439-47

Lipophosphoglycan (LPG) is the major surface glycoconjugate of 
Leishmania donovani promastigotes. The repeating disaccharide-phosphate 
units of LPG are crucial for promastigote survival inside macrophages 
and establishment of infection. LPG has a number of effects on the host 
cell, including inhibition of PKC activity, inhibition of nitric oxide 
production and altered expression of cytokines. LPG also inhibits 
phagosomal maturation, a process requiring depolymerization of 
periphagosomal F-actin. In the present study, we have characterized the 
dynamics of F-actin during the phagocytosis of L. donovani promastigotes
 in J774 macrophages. We observed that F-actin accumulated progressively
 around phagosomes containing wild-type L. donovani promastigotes during
 the first hour of phagocytosis. Using LPG-defective mutants and yeast 
particles coated with purified LPG, we obtained evidence that this 
effect could be attributed to the repeating units of LPG. LPG also 
disturbed cortical actin turnover during phagocytosis. The LPG-dependent
 accumulation of periphagosomal F-actin correlated with an impaired 
recruitment of the lysosomal marker LAMP1 and PKCalpha to the phagosome
. Accumulation of periphagosomal F-actin during phagocytosis of L. 
donovani promastigotes may contribute to the inhibition of phagosomal 
maturation by physically preventing vesicular trafficking to and from 
the phagosome.




PMID: 11254581
 

TITLE: Stage-dependent role of nitric oxide in control of Trypanosoma cruzi
infection.

AUTHORS: M Saeftel, B Fleischer, A Hoerauf

AFFILIATION: Department of Immunology, Bernhard Nocht Institute for Tropical
Medicine, 20359 Hamburg, Germany.

REFERENCE: Infect Immun 2001 Apr 69(4):2252-9

Trypanosoma cruzi, the causative agent of Chagas' disease, is known to 
be susceptible to nitric oxide (NO)-dependent killing by gamma 
interferon-activated macrophages. Mice deficient for inducible nitric 
oxide synthase (iNOS) are highly susceptible to T. cruzi, and inhibition
 of iNOS from the beginning of infection was reported to lead to an 
increase in trypomastigotes in the blood and to high mortality. In the 
present study, we investigated whether NO production is essential for 
the control of T. cruzi in all phases of the infection. BALB/c mice were
 treated at different time intervals after T. cruzi infection with an 
iNOS inhibitor, aminoguanidine or L-N6-(1-iminoethyl)-lysine (L-NIL). 
Treatment initiated with the beginning of the infection resulted in 100
% mortality by day 16 postinfection (p.i.). If treatment was started 
later during the acute phase at the peak of parasitemia (day 20 p.i.), 
all the mice survived. Parasitemia was cleared and tissue amastigotes 
became undetectable in these mice even in the presence of the iNOS 
inhibitor L-NIL. Inhibition of iNOS in the chronic phase of the 
infection, i.e., from day 60 to day 120 p.i., with L-NIL did not result 
in a reappearance of parasitemia. These data suggest that while NO is 
essential for T. cruzi control in the early phase of acute infection, it
 is dispensable in the late acute and chronic phase, revealing a 
fundamental difference in control mechanisms compared to those in 
infections by other members of the order Kinetoplastida, e.g., 
Leishmania major.




PMID: 11083765
 

TITLE: Leishmania major reaches distant cutaneous sites where it persists
transiently while persisting durably in the primary dermal site and its
draining lymph node: a study with laboratory mice.

AUTHORS: L Nicolas, S Sidjanski, J H Colle, G Milon

AFFILIATION: Unité d'Immunophysiologie et Parasitisme Intracellulaire,
Institut
Pasteur, 75724 Paris Cedex 15, France. lnicolas at pasteur.fr

REFERENCE: Infect Immun 2000 Dec 68(12):6561-6

So far, studies of Leishmania persistence in mice have used injections 
of parasites administered either intravenously in the tail vein or 
subcutaneously in the footpad. These routes poorly reflect the natural 
conditions when the sandfly delivers metacyclic promastigotes 
intradermally. In this study B10D2 and BALB/c mice were inoculated 
within the ear dermis with 10(4) Leishmania major metacyclic 
promastigotes. The parasite load was monitored by quantitative PCR in 
different tissues from the dermal inoculation site to distant tissues. 
The two sites of multiplication and persistence of parasites were the 
site of L. major inoculation and the draining lymph node (DLN), with a 
different pattern in the two mouse inbred lines. These two organs were 
the only sites harboring parasites 12 months postinoculation, with the 
DLN of BALB/c mice harboring around 10(7) parasites, a stable load from 
months 3 to 12. In these two sites, 8 and 12 months after inoculation, 
interleukin 4 (IL-4), gamma interferon, and inducible nitric oxide 
synthase transcripts parallel the parasite load while IL-10 transcript 
levels remain high. In addition, at early time points until month 3, 
parasite DNA was also detected in distant tissues such as the 
contralateral noninoculated ear or the tail skin, indicating that blood 
was at least transiently disseminating the parasites. In contrast, L. 
major DNA in liver, spleen, and femoral bone marrow remained sporadic in
 mice of both lines. This study is discussed within the framework of 
Leishmania transmission from the vertebrate host to the sandfly vector, 
a complex process still poorly understood.




PMID: 11034408
 

TITLE: Cyclooxygenase-2 expression in macrophages: modulation by protein kinase
C-alpha.

AUTHORS: M Giroux, A Descoteaux

AFFILIATION: Institut National de la Recherche Scientifique-Institut
Armand-Frappier, Université du Québec, Laval, Canada.

REFERENCE: J Immunol 2000 Oct 165(7):3985-91

Cyclooxygenase-2 (COX-2) is an inducible enzyme responsible for high 
levels of PG production during inflammation and immune responses. 
Previous studies with pharmacological inhibitors suggested a role for 
protein kinase C (PKC) in PG production possibly by regulating COX-2 
expression. In this study, we addressed the role of PKC-alpha in the 
modulation of COX-2 expression and PGE2 synthesis by the overexpressing 
of a dominant-negative (DN) mutant of this isoenzyme in the mouse 
macrophage cell line RAW 264.7. We investigated the effect of various 
stimuli on COX-2 expression, namely, LPS, IFN-gamma, and the 
intracellular parasite Leishmania donovani. Whereas LPS-induced COX-2 
mRNA and protein expression were down-regulated in DN PKC-alpha-
overexpressing clones, IFN-gamma-induced COX-2 expression was up-
regulated in DN PKC-alpha-overexpressing clones with respect to normal 
RAW 264.7 cells. Measurements of PGE2 levels revealed a strong 
correlation between PGE2 secretion and IFN-gamma-induced COX-2 mRNA and 
protein levels in DN PKC-alpha-overexpressing clones. Taken together, 
these results suggest a role for PKC-alpha in the modulation of LPS- and
 IFN-gamma-induced COX-2 expression, as well as in IFN-gamma-induced 
PGE2 secretion.








PMID: 10940917
 

TITLE: Regulation of type 2 nitric oxide synthase by type 1 interferons in
macrophages infected with Leishmania major.

AUTHORS: J Mattner, H Schindler, A Diefenbach, M Röllinghoff, I Gresser, C
Bogdan

AFFILIATION: Institute of Clinical Microbiology, Immunology, and Hygiene,
University of Erlangen, Erlangen, Germany.

REFERENCE: Eur J Immunol 2000 Aug 30(8):2257-67

We recently reported that the infection of macrophages with Leishmania 
major led to the release of type 1 interferons (IFN-alpha /beta ). 
Moreover, at day 1 of infection of mice with L. major, IFN-alpha /beta 
was required for the expression of type 2 (inducible) NO synthase (NOS2 
or iNOS) which, however, was restricted to a few macrophages in the 
dermis. Here, we further characterized the regulation of NOS2 by IFN-
alpha /beta. Macrophages that were either simultaneously or sequentially
 exposed to L. major promastigotes and IFN-alpha /beta expressed NOS2 
and anti-leishmanial activity. In contrast, when high amounts of IFN-
alpha /beta were used or when IFN-alpha /beta was added to the 
macrophages 2 h prior to the parasites, almost no induction of NOS2 was 
observed. After pretreatment with IFN-alpha /beta, tyrosine 
phosphorylation and nuclear DNA binding of Stat1alpha, the degradation 
of the NF-kappaB inhibitor (IkappaBalpha and beta), and the nuclear 
translocation of NF-kappaB were strongly impaired compared with 
macrophages exposed to IFN-alpha /beta and L. major simultaneously. Thus
, IFN-alpha /beta exerts agonistic or antagonistic effects on the 
expression of NOS2 in macrophages infected with a microbial pathogen, 
depending on the sequence of the stimuli and the amount of IFN-alpha /
beta added. The limited number of NOS2-positive macrophages at day 1 of 
infection in vivo might result from a blockage of non-infected 
macrophages by IFN-alpha /beta that is released by neighboring infected 
cells.




PMID: 10586030
 

TITLE: Extracellular signal-related kinase (ERK) and p38 mitogen-activated
protein (MAP) kinases differentially regulate the lipopolysaccharide-mediated
induction of inducible nitric oxide synthase and IL-12 in macrophages:
Leishmania phosphoglycans subvert macrophage IL-12 production by targeting ERK
MAP kinase.

AUTHORS: G J Feng, H S Goodridge, M M Harnett, X Q Wei, A V Nikolaev, A P
Higson, F Y Liew

AFFILIATION: Department of Immunology, University of Glasgow, United Kingdom.

REFERENCE: J Immunol 1999 Dec 163(12):6403-12

Macrophage activation by cytokines or microbial products such as LPS 
results in the induction and release of several key immune effector 
molecules including NO and IL-12. These have been shown to play crucial 
roles in the development of immunity to intracellular pathogens such as 
Leishmania. The molecular mechanisms underlying the induction of these 
effector molecules are not fully understood. We now show that the 
extracellular signal-related kinase (ERK) and p38 mitogen-activated 
protein (MAP) kinases play differential roles in the regulation of LPS-
stimulated inducible NO synthase and IL-12 gene expression. In 
macrophages, LPS stimulates the simultaneous activation of all three 
classes of MAP kinases, ERK, c-jun N-terminal kinase, and p38, albeit 
with differential activation kinetics. However, studies using inhibitors
 selective for ERK (PD98059) and p38 (SB203580) show that while p38 
plays an essential role in the induction of inducible NO synthase, ERK 
MAP kinases play only a minor role in promoting NO generation. In 
contrast, while p38 promotes induction of IL-12 (p40) mRNA, ERK 
activation suppresses LPS-mediated IL-12 transcription. The biological 
relevance of these regulatory signals is demonstrated by our finding 
that Leishmania lipophosphoglycans, which promote parasite survival, act
 by stimulating ERK MAP kinase to inhibit macrophage IL-12 production. 
Thus, as ERK and p38 MAP kinases differentially regulate the induction 
of the macrophage effector molecules, inducible NO synthase and IL-12, 
these kinases are potential targets not only for the development of 
novel strategies to combat intracellular pathogens but also for 
therapeutic immunomodulation.




PMID: 10553077
 

TITLE: Role of protein kinase C-alpha in the control of infection by
intracellular pathogens in macrophages.

AUTHORS: A St-Denis, V Caouras, F Gervais, A Descoteaux

AFFILIATION: INRS-Institut Armand-Frappier, Université du Québec, Laval,
Canada.

REFERENCE: J Immunol 1999 Nov 163(10):5505-11

The protein kinase C (PKC) family regulates macrophage function involved
 in host defense against infection. In this study, we investigated the 
role of macrophage PKC-alpha in the uptake and subsequent fate of 
Leishmania donovani promastigotes and Legionella pneumophila infections
. To this end, we used clones of the murine macrophage cell line RAW 264
.7 overexpressing a dominant-negative (DN) mutant of PKC-alpha. While 
phagocytosis of L. donovani promastigotes was not affected by DN PKC-
alpha overexpression, their intracellular survival was enhanced by 10- 
to 20-fold at 48 h postinfection. Intracellular survival of a L. 
donovani mutant defective in lipophosphoglycan repeating units synthesis
, which normally is rapidly degraded in phagolysosomes, was enhanced by 
100-fold at 48 h postinfection. However, IFN-gamma-induced 
leishmanicidal activity was not affected by DN PKC-alpha overexpression
. Similar to macrophages from genetically resistant C57BL/6 mice, 
control RAW 264.7 cells were not permissive for the intracellular 
replication of Legionella pneumophila. In contrast, DN PKC-alpha-
overexpressing RAW 264.7 clones were phenotypically similar to 
macrophages from genetically susceptible A/J mice, as they allowed 
intracellular replication of L. pneumophila. Permissiveness to L. 
pneumophila was not the consequence of a general defect in the 
microbicidal capacities because killing of a temperature-sensitive 
mutant of Pseudomonas aeruginosa was normal in DN PKC-alpha-
overexpressing RAW 264.7 clones. Collectively, these results support a 
role for PKC-alpha in the regulation of innate macrophage functions 
involved in the control of infection by intracellular parasites.




PMID: 10417174
 

TITLE: Activation of phosphotyrosine phosphatase activity attenuates
mitogen-activated protein kinase signaling and inhibits c-FOS and nitric oxide
synthase expression in macrophages infected with Leishmania donovani.

AUTHORS: D Nandan, R Lo, N E Reiner

AFFILIATION: Department of Medicine (Division of Infectious Diseases), Faculty
of Medicine, University of British Columbia, Vancouver, British Columbia,
Canada V5Z 3J5.

REFERENCE: Infect Immun 1999 Aug 67(8):4055-63

Intracellular protozoan parasites of the genus Leishmania antagonize 
host defense mechanisms by interfering with cell signaling in 
macrophages. In this report, the impact of Leishmania donovani on 
mitogen-activated protein (MAP) kinases and nitric oxide synthase (NOS) 
expression in the macrophage cell line RAW 264 was investigated. 
Overnight infection of cells with leishmania led to a significant 
decrease in phorbol-12-myristate-13-acetate (PMA)-stimulated MAP kinase 
activity and inhibited PMA-induced phosphorylation of the MAP kinase 
substrate and transcription factor Elk-1. Simultaneously, leishmania 
infection markedly attenuated the induction of c-FOS and inducible 
nitric oxide synthase (iNOS) expression in response to PMA and gamma 
interferon (IFN-gamma), respectively. These effects correlated with 
decreased phosphorylation of p44 and p42 MAP kinases on tyrosine 
residues. Consistent with the latter finding, lysates prepared from 
leishmania-infected cells contained an activity that dephosphorylated 
MAP kinase in vitro, suggesting the possibility of a phosphatase acting 
in vivo. Attenuation of both MAP kinase activity and c-FOS and iNOS 
expression was reversed by treatment of macrophages with sodium 
orthovanadate prior to infection. It was also found that the specific 
activity of the Src homology 2 domain containing tyrosine phosphatase (
SHP-1) toward MAP kinase was markedly increased in leishmania-infected 
cells. These findings indicate that infection with L. donovani 
attenuates MAP kinase signaling and c-FOS and iNOS expression in 
macrophages by activating cellular phosphotyrosine phosphatases. This 
may represent a novel mechanism of macrophage deactivation during 
intracellular infection.




PMID: 10229665
 

TITLE: Expression and alteration of the S2 subsite of the Leishmania major
cathepsin B-like cysteine protease.

AUTHORS: V J Chan, P M Selzer, J H McKerrow, J A Sakanari

AFFILIATION: Department of Pathology, University of California, San Francisco,
CA, USA.

REFERENCE: Biochem J 1999 May 340 ( Pt 1)():113-7

The mature form of the cathepsin B-like protease of Leishmania major (
LmajcatB) is a 243 amino acid protein belonging to the papain family of 
cysteine proteases and is 54% identical to human-liver cathepsin B. 
Despite the high identity and structural similarity with cathepsin B, 
LmajcatB does not readily hydrolyse benzyloxycarbonyl-Arg-Arg-7-amino-4-
methyl coumarin (Z-Arg-Arg-AMC), which is cleaved by cathepsin B enzymes
. It does, however, hydrolyse Z-Phe-Arg-AMC, a substrate typically 
cleaved by cathepsin L and B enzymes. Based upon computer generated 
protein models of LmajcatB and mammalian cathepsin B, it was predicted 
that this variation in substrate specificity was attributed to Gly234 at
 the S2 subsite of LmajcatB, which forms a larger, more hydrophobic 
pocket compared with mammalian cathepsin B. To test this hypothesis, 
recombinant LmajcatB was expressed in the Pichia pastoris yeast 
expression system. The quality of the recombinant enzyme was confirmed 
by kinetic characterization, N-terminal sequencing, and Western blot 
analysis. Alteration of Gly234 to Glu, which is found at the 
corresponding site in mammalian cathepsin B, increased recombinant 
LmajcatB (rLmajcatB) activity toward Z-Arg-Arg-AMC 8-fold over the wild-
type recombinant enzyme (kcat/Km=3740+/-413 M-1.s-1 versus 472+/-72.4 M-
1.s-1). The results of inhibition assays of rLmajcatB with an inhibitor 
of cathepsin L enzymes, K11002 (morpholine urea-Phe-homoPhe-
vinylsulphonylphenyl, kinact/Ki=208200+/-36000 M-1. s-1), and a 
cathepsin B specific inhibitor, CA074 [N-(L-3-trans-
propylcarbamoyloxirane-2-carbonyl)-l-isoleucyl-l- prolin e, kinact/Ki=
199200+/-32900 M-1.s-1], support the findings that this protozoan 
protease has the P2 specificity of cathepsin L-like enzymes while 
retaining structural homology to mammalian cathepsin B.




PMID: 9916929
 

TITLE: Expression of inducible nitric oxide synthase in human granulomas and
histiocytic reactions.

AUTHORS: F Facchetti, W Vermi, S Fiorentini, M Chilosi, A Caruso, M Duse, L D
Notarangelo, R Badolato

AFFILIATION: Department of Pathology, University of Brescia, Italy.
facchett at master.cci.unibs.it

REFERENCE: Am J Pathol 1999 Jan 154(1):145-52

Inducible nitric oxide synthase (iNOS) is required in immune response 
against infections and is involved in granuloma formation in animals; in
 murine macrophages, iNOS is induced by lipopolysaccharide and 
interferon-gamma. In contrast, the role of iNOS in human immune response
 against infections is still questioned, and its expression in 
granulomas is poorly investigated. Using Western blotting and 
immunohistochemistry, we investigated iNOS expression in human lymph 
nodes with nonspecific reactions and in tissues containing granulomas 
caused by mycobacteria, Toxoplasma, Cryptococcus neoformans, Leishmania
, Bartonella, noninfectious granulomas (sarcoidosis, foreign body), and 
other hystiocitic reactions (Kikuchi's disease, Omenn syndrome). iNOS 
was undetectable in nonspecific reactive lymphadenitis, foreign-body 
granulomas, and Omenn syndrome, whereas it was strongly expressed in 
infectious granulomas, sarcoidosis, and Kikuchi's diseases. 
Immunohistochemistry demonstrated that iNOS was selectively expressed by
 the epithelioid and multinucleated giant cells within the granulomas. 
Use of an anti-nitrotyrosine antibody, recognizing nitrosilated amino 
acid residues derived from nitric oxide production, revealed a 
consistent positivity within the cells expressing iNOS, thus suggesting 
that iNOS is functionally active. Detection of cytokines by reverse 
transcriptase-polymerase chain reaction demonstrated that tissues that 
were positive for iNOS, also expressed the Thl-type cytokine interferon-
gamma mRNA, but not the Th2-type cytokine interleukin-4. Taken together
, these results indicate that iNOS is involved in different human immune
 reactions characterized by histiocytic/granulomatous inflammation and 
associated with Th1-type cytokine secretion.








PMID: 9862342
 

TITLE: Nitric oxide regulates Th1 cell development through the inhibition of
IL-12 synthesis by macrophages.

AUTHORS: F P Huang, W Niedbala, X Q Wei, D Xu, G J Feng, J H Robinson, C Lam, F
Y Liew

AFFILIATION: Department of Immunology, University of Glasgow, GB.

REFERENCE: Eur J Immunol 1998 Dec 28(12):4062-70

We have previously reported that mice lacking inducible nitric oxide 
synthase (NOS2) developed enhanced Th1 cell responses. We now 
investigated the mechanism by which NO modulates Th1 cells 
differentiation. Peritoneal macrophages from NOS2-deficient mice 
infected with Leishmania major in vivo or stimulated with IFN-gamma or 
lipopolysaccharide (LPS) in vitro produced significantly higher levels 
of IL-12 than those from heterozygous or wild-type mice. A macrophage 
cell line, J774, produced significant amounts of IL-12 following 
activation with LPS, or LPS plus IFN-gamma. This could be markedly 
enhanced by the NOS inhibitor L-NG monomethyl arginine (L-NMMA), but 
profoundly inhibited by the NO-generating compound S-nitroso-N-acetyl-
penicillamine (SNAP). The effect of NO in this system is selective, 
since SNAP enhanced and L-NMMA decreased TNF-alpha synthesis by LPS-
activated J774 cells. The differential effect of NO on IL-12 and TNF-
alpha is at the transcriptional level and is activation dependent. Since
 IL-12 is a major inducer of Th1 cells which produce IFN-gamma that can 
activate macrophages to produce IL-12, our data demonstrate that NO can 
be an inhibitor of this feedback loop, preventing the excessive 
amplification of Th1 cells which are implicated in a range of 
immunopathologies.




PMID: 9725234
 

TITLE: Migration inhibitory factor induces killing of Leishmania major by
macrophages: dependence on reactive nitrogen intermediates and endogenous
TNF-alpha.

AUTHORS: S Jüttner, J Bernhagen, C N Metz, M Röllinghoff, R Bucala, A Gessner

AFFILIATION: Institute of Clinical Microbiology and Immunology, University of
Erlangen-Nürnberg, Germany.

REFERENCE: J Immunol 1998 Sep 161(5):2383-90

Macrophage migration inhibitory factor (MIF) is a product of activated T
 cells, anterior pituitary cells, and macrophages. MIF plays an 
important role in LPS-induced shock and delayed-type hypersensitivity. 
Furthermore, MIF exhibits a proinflammatory spectrum of action, 
promoting TNF-alpha production by macrophages, and counter-regulates 
glucocorticoid suppression of cytokine production. Here, we report that 
purified recombinant MIF activates murine macrophages to kill Leishmania
 major, with maximal effects at concentrations above 1 microg/ml. This 
MIF-mediated activation is specific, since it can be blocked completely 
by anti-MIF mAb. The MIF-mediated activation is dependent on TNF-alpha 
produced endogenously by macrophages, because the administration of anti
-TNF-alpha antiserum markedly reduced the MIF effect. No MIF-mediated 
activation was observed in macrophages derived from TNF receptor p55 
knockout mice, thus demonstrating the requirement of the smaller TNF 
receptor molecule for autocrine TNF-alpha signaling. A highly specific 
inhibitor of the inducible nitric oxide synthase (iNOS), L-N6-(1-
iminoethyl)lysine, dihydrochloride, also inhibited the action of MIF, 
suggesting an important role for iNOS in the antiparasitic properties of
 MIF. In line with this, no MIF-mediated activation was detected 
analyzing macrophages derived from iNOS-deficient mice. The effect of 
MIF was blocked completely by the macrophage-deactivating cytokines IL-
10, IL-13, and TGF-beta. Finally, the expression of MIF mRNA and protein
 was up-regulated in lymph nodes of mice during the first week after 
infection with L. major. MIF therefore represents a cytokine involved 
not only in the recruitment of proinflammatory cells during infection 
but also in the complex regulation of the antimicrobial activity of 
these cells.




PMID: 9712819
 

TITLE: Paclitaxel (Taxol)-induced killing of Leishmania major in murine
macrophages.

AUTHORS: T M Doherty, A Sher, S N Vogel

AFFILIATION: Immunobiology Section, Laboratory of Parasitic Diseases, National
Institute of Allergy and Infectious Diseases, National Institutes of Health,
Bethesda, Maryland 20892, USA.

REFERENCE: Infect Immun 1998 Sep 66(9):4553-6

The antitumor drug paclitaxel (Taxol) has been demonstrated to be a 
lipopolysaccharide mimetic in murine macrophages. In this study, the 
capacity of paclitaxel to activate macrophages to become microbicidal 
for Leishmania major was examined. Paclitaxel and gamma interferon 
synergized to kill intracellular L. major in Lpsn, but not Lpsd, 
macrophages by a nitric oxide (NO.)-dependent mechanism.




PMID: 9637515
 

TITLE: Mechanisms of macrophage stimulation through CD8: macrophage CD8alpha
and
CD8beta induce nitric oxide production and associated killing of the parasite
Leishmania major.

AUTHORS: N Hirji, T J Lin, E Bissonnette, M Belosevic, A D Befus

AFFILIATION: Department of Medicine, University of Alberta, Edmonton, Canada.

REFERENCE: J Immunol 1998 Jun 160(12):6004-11

Prior studies demonstrated that rat macrophages express CD8, which 
differs from T lymphocyte CD8 within the ligand binding domain. We 
investigated whether stimulation of macrophage CD8 could induce mediator
 release and regulate host defense. Cross-linking either CD8alpha (OX8, 
5 microg/ml) or CD8beta (341, 10 microg/ml) stimulated nitric oxide (NO
) production, which correlated with an up-regulation of inducible NO 
synthase protein. Cell signaling inhibitors were used to elucidate the 
pathways of CD8alpha and CD8beta stimulation. Genistein (broad spectrum 
protein tyrosine kinase inhibitor, 10 microg/ml), PP1 (src family kinase
 inhibitor, 5 microg/ml), polymyxin B (protein kinase C (PKC) inhibitor
, 100 microg/ml), and Ro 31-8220 (PKC inhibitor, 1 microM) significantly
 inhibited anti-CD8alpha- and anti-CD8beta-stimulated NO production and 
inducible NO synthase up-regulation, suggesting that tyrosine kinase(s
) (src family) and PKC are involved in CD8 signaling. In addition, cross
-linking CD8alpha stimulated NO-dependent macrophage killing of the 
parasite Leishmania major. For the first time, this work demonstrates 
that the beta-chain of macrophage CD8, in addition to the alpha-chain, 
can regulate mediator release. These results further illustrate the 
importance of this molecule and support our previous data demonstrating 
differences between macrophage and T lymphocyte CD8. Additional studies 
on the signaling mechanisms and possible ligand(s) for macrophage CD8 
will lead to a greater understanding of inflammation and host defense.




PMID: 9412471
 

TITLE: Cytoskeletal association is important for differential targeting of
glucose transporter isoforms in Leishmania.

AUTHORS: E L Snapp, S M Landfear

AFFILIATION: Department of Molecular Microbiology and Immunology, Oregon Health
Sciences University, Portland, Oregon 97201, USA.

REFERENCE: J Cell Biol 1997 Dec 139(7):1775-83

The major glucose transporter of the parasitic protozoan Leishmania 
enriettii exists in two isoforms, one of which (iso-1) localizes to the 
flagellar membrane, while the other (iso-2) localizes to the plasma 
membrane of the cell body, the pellicular membrane. These two isoforms 
differ only in their cytosolic NH2-terminal domains. Using immunoblots 
and immunofluorescence microscopy of detergent-extracted cytoskeletons, 
we have demonstrated that iso-2 associates with the microtubular 
cytoskeleton that underlies the cell body membrane, whereas the 
flagellar membrane isoform iso-1 does not associate with the 
cytoskeleton. Deletion mutants that remove the first 25 or more amino 
acids from iso-1 are retargeted from the flagellum to the pellicular 
membrane, suggesting that these deletions remove a signal required for 
flagellar targeting. Unlike the full-length iso-1 protein, these 
deletion mutants associate with the cytoskeleton. Our results suggest 
that cytoskeletal binding serves as an anchor to localize the iso-2 
transporter within the pellicular membrane, and that the flagellar 
targeting signal of iso-1 diverts this transporter into the flagellar 
membrane and away from the pellicular microtubules.




PMID: 2476435
 

TITLE: Wild-type and drug-resistant Leishmania major hydrolyze methotrexate to
N-10-methyl-4-deoxy-4-aminopteroate without accumulation of methotrexate
polyglutamates.

AUTHORS: T E Ellenberger, J E Wright, A Rosowsky, S M Beverley

AFFILIATION: Department of Biological Chemistry and Molecular Pharmacology,
Harvard Medical School, Boston, Massachusetts.

REFERENCE: J Biol Chem 1989 Sep 264(27):15960-6

We have examined the metabolism of the folate analog methotrexate (MTX) 
in the human parasite Leishmania major. These cells readily hydrolyzed 
MTX to N-10-methyl-4-deoxy-4-aminopteroate (MAPA), such that following a
 24-h incubation in 1 microM [3H]MTX approximately 30% of the cell-
associated radioactivity was MAPA. MAPA also accumulated in the culture 
medium, exceeding the concentration of MTX after 24 h. Neither 7-hydroxy
-methotrexate nor MTX polyglutamates were observed in cells or medium, 
even after a 72-h incubation with MTX. In contrast to MTX, folate is 
extensively polyglutamylated in L. major (Santi, D. V., Nolan, P., and 
Shane, B. (1987) Biochem. Biophys. Res. Commun. 146, 1089-1092). MAPA 
was found to be 190-fold less potent than MTX as an inhibitor of 
leishmanial growth and to bind less tightly than MTX to leishmanial 
dihydrofolate reductase-thymidylate synthase. We therefore examined the 
possibility that MTX resistance is mediated by increased MTX hydrolysis 
to MAPA in drug-resistant Leishmania. However, enzymatic assays show 
that the rate of MTX hydrolysis was unaltered in the MTX-resistant R1000
-3 line and the primaquine-resistant PQ-R30 line (which is 24-fold cross
-resistant to MTX). In addition to MAPA, several minor unidentified 
metabolites were observed in the LT252, R1000-5B, and PQR30 cells but no
 consistent differences in the amounts of these metabolites were evident
 among these lines. These data indicate that alterations in the rate of 
MTX hydrolysis in vitro, or in the characteristics of MTX metabolites 
formed in vivo, do not underly the MTX resistance displayed by the H 
region-amplified R1000-5B and PQ-R30 lines.




REQUEST: [ sand fly ]

(6 articles match this request. 5 articles matching other requests removed)



PMID: 15707279
 

TITLE: Landscape associations of the sand fly, Lutzomyia (Heleocyrtomyia)
apache
(Diptera: Psychodidae), in the southwestern United States: a geographic
information system analysis.

AUTHORS: M V Herrero, W E Yarnell, E T Schmidtmann

AFFILIATION: School of Veterinary Medicine, Universidad Nacionale, Herredia,
Costa Rica.

REFERENCE: J Vector Ecol 2004 Dec 29(2):205-11

Landscape associations of the sand fly, Lutzomyia apache, Young and 
Perkins, in the southwestern U.S. were investigated by light/suction 
trap sampling and the development of a GIS-generated distribution map. 
In the mid-Rio Grande River valley, N.M., female and male L. apache were
 captured in updraft light/suction traps set in desert shrubland, 
irrigation levee, and bosque vegetation communities. Small numbers of 
flies were captured, but the presence of males and females in spatially 
separate and diverse plant communities at two locations suggest that L. 
apache are dispersed among available vegetation types. These data, along
 with 22 previously published collection site records, were used with a 
suite of physiographic features to characterize the biogeographic 
conditions suitable for L. apache. Suitable conditions encompass three 
life zones: the Rocky Mountain steppe province, the Colorado semi-
plateau province, and the American semi-desert province, all within the 
dry domain region of the western U.S. The potential range of L. apache 
was then estimated based on elevation, mean and max - min temperature, 
precipitation, wet days, and relative humidity. The estimated range 
includes large contiguous areas in north-central Colorado, east-central 
New Mexico and west Texas, the lower mid-Rio Grande River valley, and 
southern Arizona, along with smaller, patchy, areas in northern Arizona
, California, Nevada, Utah, and central Idaho. The spatial relationship 
between the estimated distribution of L. apache and the location of 
livestock exposed to vesicular stomatitis virus at the onset of recent 
outbreaks is presented.




REQUEST: [ sandfly ]

(3 articles match this request. 3 articles matching other requests removed)














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