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1
*
Institute of Clinical Microbiology and Immunology, University of Erlangen-Nürnberg, Erlangen; and
Laboratory of Biochemistry, Chair for Interfacial Engineering, University of Stuttgart, Stuttgart, Germany; and
The Picower Institute for Medical Research, Manhasset, NY 11030
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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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 µg/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- produced
endogenously by macrophages, because the administration of
anti-TNF- 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- 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-ß. 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. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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MIF acts as a profound counter-regulator of the anti-inflammatory
and immunosuppressive effects of glucocorticoids (11). Recently, MIF
has been demonstrated to be induced by glucocorticoids, and recombinant
MIF has been shown to override glucocorticoid inhibition of
proinflammatory cytokines, such as TNF-, IL-1ß, IL-6, and IL-8 in
LPS-stimulated human monocytes (14). Also, a proinflammatory spectrum
of action for MIF has been verified. MIF induces TNF- and IL-8
secretion by macrophages (7) or in bronchoalveolar lavage cells,
respectively (15). Recombinant MIF in concert with other
proinflammatory cytokines, such as IFN-
, has been found to promote
macrophage nitric oxide (NO) release (10). In an immunologically
induced kidney disease in the rat, anti-MIF Ab resulted in a marked
inhibition of disease progression and iNOS expression (16). Various
proinflammatory stimuli, such as LPS, TNF-, and IFN-, were potent
inducers of MIF secretion (6). Previous reports that a cloned species
of human MIF activates macrophages to kill Leishmania
donovani had to be retracted due to PHA contamination of the
MIF-containing COS cell supernatants employed (17, 18).
The function of macrophages, the most important effector cells in
murine leishmaniasis, is determined by a variety of cytokines, mainly
produced by T cells (for review, see Refs. 19 and 20). While the
Th1-specific cytokine IFN- has been shown to activate macrophages to
synthesize iNOS and thus to enhance the killing of intracellular
leishmania amastigotes, the Th2 cytokines IL-4 and IL-10 have been
demonstrated to deactivate these effector functions of macrophages.
Mice developing a Th1 response to cutaneous leishmaniasis are able to
control the local lesion, whereas mice with a predominant Th2 answer
cannot restrict the parasite replication and die of visceral
leishmaniasis (19, 20). MIF has recently been identified as a cytokine
produced by mitogen-stimulated Th2, but not Th1 cell clones (21). Among
the MIF-producing T cell clones examined was L1/1, a T cell clone
specific for Leishmania major (22). Therefore, it was the
aim of this study to analyze whether MIF is able to influence the
leishmanicidal effector functions of macrophages in vitro. Using murine
macrophages infected with L. major, we examined 1) the
effect of MIF on leishmanicidal effector functions of the host cells of
this protozoan parasite, 2) the mechanism by which the leishmanicidal
effect is mediated, and 3) the possible influence of known
macrophage-deactivating cytokines, such as IL-10, IL-13, and TGF-ß,
on MIF-induced macrophage activation.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Recombinant mouse and human MIF were cloned, expressed in
Escherichia coli, and purified by anion exchange and reverse
phase chromatography as described previously (23, 24). The LPS content
of purified recombinant MIF was <20 pg/µg protein as measured by the
QCL-1000 Limulus amebocyte lysate assay obtained from
BioWhittaker/Serva (Heidelberg, Germany), performed according to the
manufacturer’s instructions. Recombinant mouse IFN-, recombinant
murine IL-10, and recombinant murine IL-13 (LPS content of each
cytokine, <0.1 ng/µg protein) were purchased from R&D Systems
(Wiesbaden, Germany). Recombinant murine TNF- (LPS level, <0.1
ng/µg protein) was obtained from IC Chemicals (Munich, Germany).
TGF-ß (PHA, Hannover, Germany) had an LPS content of <20 pg/µg
protein. The reagents for TNF- ELISA were obtained from PharMingen
(Hamburg, Germany). Cells were cultured, and all cytokines were diluted
to the concentrations used in the experiments in C-RPMI culture medium
1640 (Biochrom, Berlin, Germany; supplemented with 2 mM glutamine, 10
mM HEPES buffer, 7.5% NaHCO3, 0.05 mM 2-ME, 100 µg/ml
penicillin, 160 µg/ml gentamicin, and 10% selected FCS with a total
LPS content <100 pg/ml).
LPS (E. coli serotype O127:B8) was purchased from Sigma
(Munich, Germany). L-NIL was obtained from Calbiochem (San
Diego, CA). Murine anti-mouse MIF mAb was generated as described
previously (16, 25). Murine IgG (Sigma) was used as an isotype control.
Rabbit antiserum raised against recombinant mouse TNF- was provided
by Dr. H. U. Beuscher (Erlangen, Germany). Rabbit antiserum was
generated against recombinant mouse IL-10 as described previously (26).
Rabbit preimmune serum served as control serum.
Mice and parasites
Female mice of the inbred strains BALB/c, C57BL/6, and C3H/HeJ were obtained from Charles River Breeding Laboratories (Sulzfeld, Germany). TNFR55-/- mice (27) as well as sex- and age-matched control animals were gifts from Dr. Klaus Pfeffer (Munich, Germany); iNOS-/- mice (28) as well as sex- and age-matched control animals were provided by Dr. Christian Bogdan (Erlangen, Germany).
L. major promastigotes of the strain MHOM/IL/81/FEBNI were grown in vitro in blood agar cultures as described previously (29). Stationary phase promastigotes were washed in PBS and were added to the macrophage cultures as indicated below.
Preparation of cells
T cell-free macrophage monolayers were prepared and tested for purity as described in detail previously (30, 31). Briefly, thioglycolate-elicited peritoneal exudate cells (PEC) were washed twice and resuspended in C-RPMI culture medium, seeded into Lab-Tek tissue culture chamberslides (2 x 105 cells/chamber; Nunc, Wiesbaden, Germany), and allowed to adhere for 3 to 4 h (37°C, 5% CO2, 95% air humidity); thereafter, nonadherent cells were removed by three extensive washings with culture medium.
Bone marrow-derived macrophages (BMM) were prepared essentially as described previously (30, 32). Cells were prepared from femurs of mice, and after 3 days in culture, nonadherent progenitor cells were taken and cultured for an additional 7 days in culture medium supplemented with 30% (v/v) L cell-conditioned medium as a source of CSF-1. Adherent BMM were harvested with a rubber policemen and seeded into Lab-Tek tissue chamberslides.
Stimulation of macrophages, infection, and assessment of intracellular parasites
Before infection, macrophage cultures were incubated in culture medium or in culture medium containing cytokine(s), anti-cytokine Abs, or reagents for a standard time of 4 h (in some experiments a different incubation time was used, as indicated in the text). Macrophages were then infected with L. major promastigotes (parasite/cell ratio, 10:1) for 4 h. Thereafter, nonphagocytosed parasites were washed off, and the cultures were further incubated in the presence or the absence of cytokines and Abs for 72 to 96 h. Intracellular live amastigotes were assessed after staining with ethidium bromide (50 µg/ml) and acridine orange (5 µg/ml) in PBS by fluorescence photography as described in detail previously (30). The percentage of infected macrophages (mean ± SD) of three or four different cultures were tested for statistical significance by Student’s t test for unpaired samples (two-tailed).
Measurement of NO2- secretion
The nitrite concentration was measured by a microplate assay method with Griess reagent (1% sulfanilamide/0.1% naphthylethylene diamine dihydrochloride/2.5% H3PO4) as previously described (33).
Analysis of MIF mRNA and protein expression during the course of L. major infection of C57/BL6 and BALB/c mice
Female mice of the inbred strain BALB/c and C57BL/6 at 6 to 12 wk of age were infected with 2 x 106 L. major promastigotes in volume of 50 µl intradermally. After RNA extraction by use of acidic guanidinium thiocyanate (34) from lymph nodes or skin at the time points indicated, the levels of MIF mRNA were quantified applying the RiboQuant multiprobe RNase protection assay kit mCK-2b (PharMingen, San Diego, CA) according to the manufacturer’s instruction. Ten micrograms of total RNA from tissues of two mice per group and time point were analyzed in each reaction, and the intensities of the resulting bands were quantified with a BAS 2000 Bioimager (Fuji, Tokyo, Japan) and TINA 2.0 software (Raytest, Straubenhardt, Germany).
Total lymph node cells of leishmania-infected C57BL/6 or BALB/c mice were cultured for 72 h in vitro at a density of 2 x 106 cells/ml in the presence or the absence of L. major freeze/thawed promastigote Ag (Lsh Ag; 5 x 106 cell equivalents/ml) or concanavalin A at a concentration of 7.5 µg/ml (Sigma). For measurements of MIF, protein-conditioned media were analyzed by sandwich ELISA employing a monoclonal anti-MIF capture Ab, a polyclonal rabbit anti-mouse MIF detector, and purified mouse rMIF as standard as described previously (14).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Recombinant human as well as mouse MIF significantly reduced the
percentage of infected cells and the number of parasites per 100
macrophages (BALB/c PEC) in a dose-dependent manner (Fig. 1
). The fact that MIF stimulates PEC of
LPS-insensitive C3H/HeJ mice to the same extent (70 ± 2.4%
infected PEC in the medium control compared with 48 ± 1.7%
infected PEC cultured with 2.5 µg/ml murine MIF) as PEC of BALB/c and
C57/BL6 mice excludes macrophage activation mediated by low levels of
LPS (<20 pg/µg MIF). The MIF dose necessary for a significant
reduction exceeded 1 µg/ml. This is about 100 times higher than that
of all cytokines identified to date to enhance the leishmanicidal
effector functions of macrophages, but approximately the same MIF dose
(0.1–10 µg/ml) is required to induce TNF- and NO secretion (10)
and within the range of concentrations (e.g., up to 340 ng/ml in sera
of mice) observed during inflammation in vivo (35). Addition of
anti-MIF mAb, but not control mAb, completely reversed the
stimulatory effect of murine MIF, demonstrating the specificity of the
observed macrophage activation (Fig. 2,
A and B). Furthermore, MIF enhanced the killing
of L. major in BMM of BALB/c and C57BL/6 mice, although in
these cells the overall infection rate was markedly reduced (Fig. 2E). As demonstrated in Figure 2, C and
D, experiments with kinetic assessment (24, 48, 72, and
96 h post-L. major infection) revealed that the MIF
effect was particularly evident late after infection (e.g., 72 and
96 h). MIF also induced killing of parasites in the presence of
the IFN--neutralizing Ab R4.6A2, which was capable of blocking the
activity of 10 ng/ml of rIFN-. Furthermore, there was no significant
difference in the effect of an isotype-matched control mAb and that of
the R4.6A2 mAb on MIF-induced Leishmania killing (data not
shown). Thus, we could exclude a functionally significant contribution
of IFN- produced by (very low) numbers of contaminating T or NK
cells on the MIF effects on cultured macrophages. The finding that the
simultaneous addition of IFN- together with MIF resulted in a much
more pronounced activation of macrophages (11 ± 3% of L.
major-infected cells) than optimal concentrations of either of the
cytokines alone further argues for an IFN--independent effect of
MIF.
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and reactive nitrogen endogenously produced by macrophages
MIF has previously been demonstrated to promote the release of
TNF- from RAW 264.7 macrophages and in concert with IFN- to
induce the release of NO (10). Therefore, we next asked whether the
MIF-mediated activation of macrophages to kill L. major
amastigotes was dependent on endogenously produced TNF- and/or NO.
MIF induced the production of detectable amounts of TNF- (60 ±
18 pg/ml) in cultures of L. major-infected PEC. As
demonstrated in Figure 3B, administration of
anti-TNF- antiserum, but not of a control serum, markedly
reduced MIF-mediated macrophage activation. For TNF-, two different
receptor molecules (TNF-R; molecular masses, 55 and 75 kDa) have been
described in mice (36). The roles of these two receptors in
TNF--mediated cytotoxity and antimicrobial effector function are not
yet fully understood and remain a topic of controversial discussion
(37, 38, 39, 40). To determine the role of the smaller TNF-R molecule, we
studied the PEC of TNF-R55-/- mice. Unlike the PEC of
wild-type control mice, L. major killing was not enhanced
after stimulation with MIF in TNF-R55-/- macrophages.
Consistent with this, in the receptor-deficient cells there was no
synergistic effect of exogenously added TNF- and IFN-, in
contrast to wild-type PEC (Fig. 4). These
findings demonstrate the crucial role of endogenously produced TNF-
and the requirement of the 55-kDa TNF-R molecule for the MIF-mediated
activation.
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A). In line with this
observation, MIF does not enhance leishmania killing in PEC obtained
from iNOS-deficient mice (28) (provided by Dr. C. Bogdan at our
institute; data not shown). Thus, we deduce that reactive nitrogen
metabolites generated endogenously by macrophages play an essential
role in MIF-mediated enhancement of the leishmanicidal effector
function. However, in agreement with findings reported by Bernhagen et
al. (10), no significant elevation of the NO concentration was measured
in supernatants from MIF-stimulated macrophages compared with
unstimulated macrophages. By contrast, stimulation with IFN- and MIF
resulted in a marked increase in nitrite levels (32.1 ± 3.3 µM)
compared with those in supernatants stimulated with IFN- alone
(17.2 ± 2.0 µM). Inhibition of MIF-mediated killing of L. major by IL-10, IL-13, and TGF-ß
Following infection with L. major, a complex network of
different cytokines become expressed that has only been partially
defined (19, 20). Thus, we examined whether MIF-mediated macrophage
activation could be inhibited by cytokines known to inhibit the effect
of stimulatory cytokines, e.g., IL-10, IL-13, and TGF-ß, since these
mediators have been shown to impair the intracellular killing of
leishmania in vitro (26, 41, 42). In addition, these cytokines are
secreted by Th2 cells (IL-10, IL-13) and macrophages (IL-10, TGF-ß),
cells that are also important sources of MIF (1, 2, 6, 43, 44, 45, 46, 47).
TGF-ß, IL-13, and IL-10 completely inhibited MIF-mediated activation
of the leishmanicidal effector function (Fig. 5). Secretion of IL-10 by T cells occurs
relatively late after stimulation (47), in contrast to MIF which is
released as early as 2 h after T cell activation (21). Therefore,
in a further set of experiments, the time dependence of the
IL-10-mediated macrophage deactivation was examined. IL-10 was most
effective when added 4 h before MIF. When added simultaneously
with or 4 h after MIF, the deactivating effect of IL-10 was
markedly decreased. IL-10 did not exhibit any measurable inhibition of
leishmania killing when PEC had been activated previously with MIF for
12 h (Fig. 5, A and B). To evaluate the role
of autocrine IL-10 produced by PEC, endotoxin-free anti-IL-10
antiserum was added simultaneously with MIF to the leishmania-infected
macrophages. In contrast to control preimmune serum, a significant
further reduction of infected macrophages (18 ± 6%) was
observed, suggesting an inhibitory influence of endogenously produced
IL-10 as previously reported for other macrophage stimulatory cytokines
(26).
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To evaluate whether MIF is expressed after L.
major infection in vivo, thereby contributing to the control of
the parasites in tissues of mice, we first analyzed the expression of
MIF mRNA by RNase protection assays. As depicted in Figure 6 there was a measurable up-regulation of
MIF mRNA in the lymph nodes draining the site of infection, which was
not detected in contralateral or lymph nodes of mice injected with PBS
only (data not shown). Compared with the mRNAs of other cytokines
measured simultaneously in the same RNase protection assays (e.g.,
IL-12 p35, IL-12 p40, IL-10, IL-1, IL-1ß, and the IL-1R
antagonist), the expression of MIF mRNA was at least 7 to 10
times higher. In addition, constitutive and similar high levels of MIF
mRNA were detected in the skin of mice, which reached approximately
50% of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA
concentrations and did not change significantly during the course of
infection (data not shown). MIF protein was also expressed by lymph
node cells stimulated in vitro with concanavalin A and leishmania Ag on
day 7 after infection, while earlier (e.g., days 0 and 2) or later
(days 14, 21, and 35) after infection the concentrations of MIF after
antigenic stimulation were below the sensitivity of the ELISA (1
ng/ml). Summarizing these findings, the expression of MIF mRNA and
protein is transiently up-regulated after infection with L.
major and may thus contribute to the control of the parasite in
vivo.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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appears to be one of the principal cytokines that activate
macrophages for enhanced killing of a variety of intracellular
parasites, including leishmania (19). Additional cytokines reported to
enhance macrophage antimicrobial activity include TNF- (31, 48),
IL-4 (49, 50), IL-3 (48), and IL-7 (30). While some of these factors
act without further stimuli, the activity of others, such as IL-4 (49)
and in some studies TNF- (31), is dependent on the presence of
synergistically stimulating factors, such as IFN-.
Only recently has pure MIF become available for study (24), and this
has been shown to promote TNF- and NO production in human murine
monocytes (10). We thus became interested in studying the capacity of
MIF to induce the killing of intracellular L. major
amatigotes. It was shown that MIF activates murine bone marrow and
peritoneally derived macrophages to inhibit the growth of and/or kill
L. major amatigotes. At its peak effective concentrations of
1.25 to 2.5 µg/ml, which are similar to levels observed in vivo (35),
MIF alone reduced the parasite burden of infected macrophage cultures
nearly as effectively as IFN-, and there was an additive effect when
MIF was administered together with suboptimal concentrations of
IFN-. As in the case of other well-studied cytokines or cytokine
combinations, MIF must be added to macrophages before or together with
the infection (30, 31, 49). This together with our observation that NO
metabolites that are produced after stimulation with MIF are crucial
for the leishmanicidal effects, argues for similar antileishmanial
effector pathways stimulated in the same way as by other
cytokines such as IFN- and IL-7 (15, 30, 49, 50, 51).
As described previously for MIF-mediated TNF- release, we found a
dose-response relationship for the leishmanicidal effect of MIF that is
unusual for a cytokine. Compared with its migration inhibitory effect
(24) as well as the glucocorticoid antagonistic properties (14, 35),
the stimulation of leishmanicidal functions required markedly higher
concentrations of MIF. To date, little is known about cellular
receptor(s) for MIF, and it remains to be determined whether different
receptor types displaying different binding affinities are responsible
for distinct thresholds for the biologic effects of MIF. Alternatively,
MIF could exert some of its biologic effects in the high dose range by
modifying target proteins at the cell surface via its described
enzymatic activities, i.e., its functioning as tautomerase (12) or
oxidoreductase (13).
Calandra et al. (6) demonstrated that MIF promotes TNF- protein
synthesis and secretion by mouse macrophages. TNF- has been
characterized in the past as a cytokine capable of enhancing the
microbicidal activity of macrophages in combination with other
cytokines (31, 48, 52). However, mice deficient for the p55 TNF-R,
although they fail to resolve lesions caused by infection with L.
major, are able to control parasite replication in vivo (39).
Thus, we wanted to test the hypothesis that endogenously produced
TNF- stimulated by MIF is involved in the macrophage killing of
leishmania. The antiparasitic effect of MIF could indeed be inhibited
significantly by the neutralization of TNF- as has been demonstrated
previously for IL-4, IL-7, IFN-, and IL-3 (30, 50, 51, 53, 54),
while TNF- alone did not enhance the leishmanicidal activity of the
PEC in our experimental setting (our unpublished observation).
The fact that there was no detectable enhancement of leishmanicidal
effector functions by MIF using cells of TNF-R p55-deficient mice
confirms the experiments using anti-TNF- Abs. In addition, these
findings demonstrate the requirement of the 55-kDa TNF-R molecule for
autocrine TNF- signaling in this system. Since TNF- added
exogenously together with MIF did not further enhance the killing of
leishmania amastigotes (data not shown), endogenously produced TNF-
does not appear to be limiting.
The severity of the disease in mice experimentally infected with L. major is genetically determined (19, 55). BALB/c mice are susceptible to L. major and develop inexorably progressive lesions with a uniform fatal outcome, while resistant C57BL/6 mice control the infection via the generation of protective CD4-positive Th1 cells (56, 57). To establish whether there are differences between the two strains of mice with regard to the responsiveness of their macrophages, MIF effects were compared on macrophages of BALB/c and C57BL/6 origins. As described for other stimulatory cytokines (31, 49), no differences between these two strains of mice were found. MIF exerted stimulatory effects on macrophages of both bone marrow and peritoneal origins with a comparable efficiency in both inbred strains. Despite the similar MIF responsiveness in the two mouse strains analyzed, there might very well be genetically determined differences in the production of MIF, as has recently been shown in different inbred strains of mice intratracheally injected with viable bacillus Calmette-Guérin (58) as well as in the case of irritant contact dermatitis (59). In this study we found MIF mRNA and protein to be up-regulated in the lymph nodes draining the site of L. major inoculation during the first days of infection in both C57BL/6 and BALB/c mice. However, measurements of MIF protein in the infected tissue in vivo, especially in the skin of mice, have to be performed to test whether there is a differential expression of MIF in the different strains of inbred mice. Shimizu et al. (60) and Bacher et al. (61) detected MIF mRNA and protein in the basal layer of normal uninflamed human epidermis. In line with, this we found MIF mRNA to be abundantly expressed in the skin of mice. Moreover, the release of MIF protein from the epidermis can be induced by proinflammatory stimuli such as LPS (61). Thus, MIF represents a factor preformed not only by T cells, macrophages, and pituitary cells but also by cells of the skin, the primary location of infections with parasites such as leishmania (19). Thus, the immediate release of preformed MIF without prior induction of synthesis could have important implications for the early, innate immune response after cutaneous infection with L. major. Firstly, as suggested by this study, MIF could directly and without other cytokines suppress the early local replication of the parasite. Secondly, MIF may inhibit the migration of monocytes that enter sites of inflammation as proposed from a recent study of MIF in a rat model of glomerulonephritis (16). It is therefore tempting to speculate that this may be one mechanism by which parasite-infected host cells are prevented from leaving the skin. By these two mechanisms MIF could contribute to the containment of parasites at the site of inoculation and prevent the systemic spread of L. major. Of special interest in this context, Laskay et al. have recently shown that the early containment of L. major is decisive for resistance to the infection and that the local restriction of parasites mediated by the innate immune system plays an important role in the development of a protective T cell response (62).
The stimulation of leishmanicidal effector functions described in this study together with other recently described immunomodulatory capacities of MIF, e.g., its T cell stimulatory effect (21) and its critical involvement in the delayed-type hypersensitivity reaction (1, 2, 63), will prompt us to evaluate the local expression of MIF in the skin of infected mice as well as to test the potential use of this cytokine in the experimental therapy of leishmaniasis in vivo.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. André Gessner, Institute of Clinical Microbiology und Immunology, Wasserturmstrasse 3, D-91054 Erlangen, Germany. E-mail address:
3 Abbreviations used in this paper: MIF, macrophage migration inhibitory factor; NO, nitric oxide; iNOS, inducible nitric oxide synthase; L-NIL, L-N6-(1-iminoethyl)lysine, dihydrochloride; PEC, peritoneal exudate cells; BMM, bone marrow-derived macrophages; Lsh Ag, leishmania antigen; TNF-R, tumor necrosis factor receptor.
Received for publication December 12, 1997. Accepted for publication April 30, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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in combination with interferon-ã, but not with interleukin 4 activates murine macrophages for elimination of Leishmania major amastigotes. Eur. J. Immunol. 20:1131.[Medline]
-mediated induction of macrophage nitric oxide generation. J. Interferon Cytokine Res. 16:1055.[Medline]
to activate murine macrophages for killing of Leishmania major amastigotes. Eur. J. Immunol. 21:327.[Medline]
production by macrophages is induced by the synergistic action of interferon (IFN)- and interleukin (IL) 4 and accounts for the antiparasitic effect mediated by IFN- and IL-4. Eur. J. Immunol. 21:1669.[Medline]
-stimulated macrophages by induction of tumor necrosis factor-. J. Immunol. 145:4290.[Abstract]
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J. L. Reyes, L. I. Terrazas, B. Espinoza, D. Cruz-Robles, V. Soto, I. Rivera-Montoya, L. Gomez-Garcia, H. Snider, A. R. Satoskar, and M. Rodriguez-Sosa Macrophage Migration Inhibitory Factor Contributes to Host Defense against Acute Trypanosoma cruzi Infection. Infect. Immun., June 1, 2006; 74(6): 3170 - 3179. [Abstract] [Full Text] [PDF]
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 A. Zicari, C. Ticconi, F. Ietta, A. Belmonte, N. Bechi, M. Realacci, M. Di Vito, F. Arcuri, M. Russo, E. Piccione, et al. Macrophage Migration Inhibitory Factor-Nitric Oxide Interaction in Human Fetal Membranes at Term Pregnancy Reproductive Sciences, May 1, 2006; 13(4): 263 - 270. [Abstract] [PDF]
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N. Pollak, T. Sterns, B. Echtenacher, and D. N. Mannel Improved Resistance to Bacterial Superinfection in Mice by Treatment with Macrophage Migration Inhibitory Factor Infect. Immun., October 1, 2005; 73(10): 6488 - 6492. [Abstract] [Full Text] [PDF]
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 A. C. Ivens, C. S. Peacock, E. A. Worthey, L. Murphy, G. Aggarwal, M. Berriman, E. Sisk, M.-A. Rajandream, E. Adlem, R. Aert, et al. The Genome of the Kinetoplastid Parasite, Leishmania major Science, July 15, 2005; 309(5733): 436 - 442. [Abstract] [Full Text] [PDF]
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 I. Cvetkovic, Y. Al-Abed, D. Miljkovic, D. Maksimovic-Ivanic, J. Roth, M. Bacher, H. Y. Lan, F. Nicoletti, and S. Stosic-Grujicic Critical Role of Macrophage Migration Inhibitory Factor Activity in Experimental Autoimmune Diabetes Endocrinology, July 1, 2005; 146(7): 2942 - 2951. [Abstract] [Full Text] [PDF]
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M. Oddo, T. Calandra, R. Bucala, and P. R. A. Meylan Macrophage Migration Inhibitory Factor Reduces the Growth of Virulent Mycobacterium tuberculosis in Human Macrophages Infect. Immun., June 1, 2005; 73(6): 3783 - 3786. [Abstract] [Full Text] [PDF]
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S. Kar, C. Metz, and D. McMahon-Pratt CD4+ T Cells Play a Dominant Role in Protection against New World Leishmaniasis Induced by Vaccination with the P-4 Amastigote Antigen Infect. Immun., June 1, 2005; 73(6): 3823 - 3827. [Abstract] [Full Text] [PDF]
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 L. Leng, C. N. Metz, Y. Fang, J. Xu, S. Donnelly, J. Baugh, T. Delohery, Y. Chen, R. A. Mitchell, and R. Bucala MIF Signal Transduction Initiated by Binding to CD74 J. Exp. Med., June 2, 2003; 197(11): 1467 - 1476. [Abstract] [Full Text] [PDF]
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 H. Koebernick, L. Grode, J. R. David, W. Rohde, M. S. Rolph, H.-W. Mittrucker, and S. H. E. Kaufmann Macrophage migration inhibitory factor (MIF) plays a pivotal role in immunity against Salmonella typhimurium PNAS, October 15, 2002; 99(21): 13681 - 13686. [Abstract] [Full Text] [PDF]
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 J. C. Delorenzi, L. Freire-de-Lima, C. R. Gattass, D. de Andrade Costa, L. He, M. E. Kuehne, and E. M. B. Saraiva In Vitro Activities of Iboga Alkaloid Congeners Coronaridine and 18-Methoxycoronaridine against Leishmania amazonensis Antimicrob. Agents Chemother., July 1, 2002; 46(7): 2111 - 2115. [Abstract] [Full Text] [PDF]
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L. Wang, H. Das, A. Kamath, L. Li, and J. F. Bukowski Human V{gamma}2V{delta}2 T Cells Augment Migration-Inhibitory Factor Secretion and Counteract the Inhibitory Effect of Glucocorticoids on IL-1{beta} and TNF-{alpha} Production J. Immunol., May 15, 2002; 168(10): 4889 - 4896. [Abstract] [Full Text] [PDF]
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 E. F. Morand, M. Leech, H. Weedon, C. Metz, R. Bucala, and M. D. Smith Macrophage migration inhibitory factor in rheumatoid arthritis: clinical correlations Rheumatology, May 1, 2002; 41(5): 558 - 562. [Abstract] [Full Text] [PDF]
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A. R. Satoskar, M. Bozza, M. Rodriguez Sosa, G. Lin, and J. R. David Migration-Inhibitory Factor Gene-Deficient Mice Are Susceptible to Cutaneous Leishmania major Infection Infect. Immun., February 1, 2001; 69(2): 906 - 911. [Abstract] [Full Text] [PDF]
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 P. L. Greenberg, V. Gordeuk, S. Issaragrisil, N. Siritanaratkul, S. Fucharoen, and R. C. Ribeiro Major Hematologic Diseases in the Developing World-- New Aspects of Diagnosis and Management of Thalassemia, Malarial Anemia, and Acute Leukemia Hematology, January 1, 2001; 2001(1): 479 - 498. [Abstract] [Full Text] [PDF]
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M. Bozza, A. R. Satoskar, G. Lin, B. Lu, A. A. Humbles, C. Gerard, and J. R. David Targeted Disruption of Migration Inhibitory Factor Gene Reveals Its Critical Role in Sepsis J. Exp. Med., January 18, 1999; 189(2): 341 - 346. [Abstract] [Full Text] [PDF]
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 J Alexander, A. Satoskar, and D. Russell Leishmania species: models of intracellular parasitism J. Cell Sci., January 9, 1999; 112(18): 2993 - 3002. [Abstract] [PDF]
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