| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
*
Max-Planck-Institut für Immunbiologie, Freiburg, Germany; and
Departamento de Bioquímica y Biología Molecular, Facultad de Veterinaria, Universidad de Extremadura, Cáceres, Spain
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
) in the context of Th1 and Th2
stimulation. Surprisingly, in the presence of either Th2 cytokines or
Th2 cells, we observe a specific induction of the hepatic isoform
arginase I in BMM. Induction of arginase I was shown on the mRNA and
protein levels and obeyed the recently demonstrated synergism among the
Th2 cytokines IL-4 and IL-10. Arginase II was detectable in
unstimulated BMM and was not significantly modulated by Th1 or Th2
stimulation. Similar to murine BMM, murine bone marrow-derived
dendritic cells, as well as a dendritic cell line, up-regulated
arginase I expression and arginase activity upon Th2 stimulation,
whereas arginase II was never detected. In addition to revealing the
unexpected expression of arginase I in the macrophage/monocyte lineage,
these results uncover a further intriguing parallelism between iNOS and
arginase: both have a constitutive and an inducible isoform, the latter
regulated by the Th1/Th2 balance. |
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
, and TNF-ß, whereas Th2
cells produce IL-4, IL-5, IL-6, IL-10, and IL-13. Accordingly, Th1
cells initiate and participate in cell-mediated immune reactions,
including the activation of inflammatory macrophages. Th2 cells are
involved in humoral immune reactions, activate mast cells and
eosinophils, and often exhibit antiinflammatory properties. A major effector pathway of inflammatory macrophages is mediated by NO that is synthesized by inducible NO synthase (iNOS)3 using L-arginine as the substrate. NO has been shown to be a crucial host-protective, anti-microbial effector molecule as well as a potential host-destructive mediator in diverse settings of immunopathology (3, 4, 5). The alternative metabolic pathway of L-arginine is catalyzed by arginase that converts L-arginine to L-ornithine and urea. Amphibians and mammals express two isoforms, arginase I and arginase II (reviewed in Ref. 6). Both isoforms catalyze the same reaction, i.e., the final step of urea synthesis in the urea cycle. Nevertheless, they are encoded by different genes, are immunologically non-cross-reactive, and differ with respect to cellular distribution and mode of regulation. Arginase I is a cytosolic enzyme, expressed almost exclusively in the liver, and acts in trimeric configuration (7). Arginase II is a mitochondrial enzyme with widespread tissue distribution, most prominently in kidney, lactating mammary gland, prostate, small intestine, and brain. Contrary to iNOS, little is known about the regulation and function of the arginases within the immune system. It has been speculated that arginase participates in the regulation of NO synthesis by competing for the common substrate L-arginine (8, 9). Other putative functions include an involvement in fibrogenic or reparative processes via collagen synthesis or antiinflammatory actions via production of polyamines (6).
In previous studies, we could demonstrate that Th1 and Th2 cytokines (9, 10) as well as the corresponding T cells (11) competitively regulate the balance of L-arginine metabolism in murine macrophages. While Th1 cells and cytokines induce iNOS and suppress arginase, Th2 cells and cytokines induce arginase and suppress iNOS. In the present study, we investigated the regulation of arginase isoforms in macrophages upon Th1 and Th2 stimulation. Furthermore, we extended our analysis to murine dendritic cells, the second major class of myeloid APCs. We demonstrate that the isoform of arginase up-regulated in murine macrophages and dendritic cells in the context of a Th2 immune response corresponds to the liver-specific enzyme, whereas the extrahepatic isoform is constitutively expressed.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
All cell cultures were performed in DMEM supplemented with 10%
heat-inactivated FCS, 2 mM L-glutamine, 60 µM 2-ME, 1 mM
sodium pyruvate, 1x nonessential amino acids, 100 U/ml penicillin, and
100 µg/ml streptomycin (Life Technologies, Paisley, U.K). Conalbumin
was purchased from Calbiochem (La Jolla, CA); L-arginine,
pigeon cytochrome c (PCC), Triton X-100,
-isonitrosopropiophenone, sulfanilamide, and N-
(1-naphthyl)ethylenediamine dihydrochloride were obtained from
Sigma (Deisenhofen, Germany). LPS (from Salmonella abortus
equi) was generously provided by Dr. C. Galanos
(Max-Planck-Institut für Immunbiologie, Freiburg, Germany).
Cytokines and animals
Recombinant murine IFN- was obtained from Genentech (South
San Francisco, CA), IL-10, GM-CSF, and TNF- from Pepro-Tech (London,
U.K.), IL-4 and IL-13 were purchased from R&D Systems (Abingdon,
U.K.).
Mice of strain AKR/N, C57BL/6, and C57BL/6 in which the IL-10 gene was deleted by homologous recombination (IL-10 KO mice) were obtained from the specific pathogen-free animal facilities of the Max-Planck-Institut and were used between 6 and 8 wk of age.
Determination of arginase activity
Arginase activity was measured in cell lysates with slight
modifications, as previously described (12). Briefly,
cells were lysed with 100 µl of 0.1% Triton X-100. After 30 min on a
shaker, 100 µl of 25 mM Tris-HCl was added. To 100 µl of this
lysate, 10 µl of 10 mM MnCl2 was added, and the
enzyme was activated by heating for 10 min at 56°C. Arginine
hydrolysis was conducted by incubating the lysate with 100 µl of 0.5
M L-arginine (pH 9.7) at 37°C for 15–120 min. The
reaction was stopped with 900 µl of
H2SO4
(96%)/H3PO4
(85%)/H2O (1/3/7, v/v/v). The urea concentration
was measured at 540 nm after addition of 40 µl
-isonitrosopropiophenone (dissolved in 100% ethanol) followed by
heating at 95°C for 30 min. One unit of enzyme activity is defined as
the amount of enzyme that catalyzes the formation of 1 µmol of urea
per min.
NO measurement
NO was measured as nitrite using the Griess reagent. Culture supernatant was mixed with 100 µl of 1% sulfanilamide, 0.1% N-(1-naphthyl)ethylenediamine dihydrochloride, and 2.5% H3PO4. Absorbance was measured at 540 nm in a microplate reader (Molecular Devices, Ismaning, Germany).
Generation of bone marrow-derived macrophages (BMM) and
dendritic cells
Bone marrow cells were obtained by flushing the femurs of mice.
Cells were cultured as previously described (13) in
hydrophobic Teflon bags (Biofolie 25; Heraeus, Hanau, Germany) in DMEM
containing 10% heat-inactivated FCS, 5% horse serum, and the
supernatant of L929 fibroblasts at a final concentration of 15% (v/v)
as a source of CSFs that drive cell proliferation toward a pure
population of BMM.
Bone marrow-derived dendritic cells (BMDC) were differentiated using a modified protocol of Inaba et al. (14). Bone marrow cells (1x106) were cultured in a final volume of 1 ml in 24-well flat-bottom plates (Costar, Cambridge, MA) in GM-CSF (5 ng/ml)-containing medium. On days 2 and 4, the plates were swirled vigorously, 750 µl medium (with nonadherent cells) were discarded and replaced with fresh GM-CSF containing medium. On day 6, when the emerging dendritic cells have already started to detach from the adherent clusters, and on day 8, 500 µl medium were carefully (without swirling the plates) replaced with fresh GM-CSF containing medium. The nonadherent cells were finally harvested on day 10.
Cells
D10G4 is a CD4+,
ßTCR+, I-Ak-restricted
Th2 T cell clone recognizing conalbumin residues 134–146
(15). AE7 is a CD4+,
ßTCR+, I-Ek-restricted
Th1 T cell clone recognizing the carboxyl-terminal fragment 81 to 104
of PCC (16). Both T cell clones were maintained by
biweekly stimulation with 30 Gy-irradiated splenocytes (AKR/N mice) and
50 µg/ml of the appropriate Ag. D2SC/1 is a retrovirally immortalized
dendritic cell line (17) that was generously provided by
Dr. P. Ricciardi-Castagnoli (Consiglio Nazionale delle Ricerche Center
of Cellular and Molecular Pharmacology, Milan, Italy).
Ag presentation assays
For determination of arginase activity and nitrite production in
BMDC-T cell cocultures (5 x 104 and 1
x 105 cells, respectively), experiments were set
up in 96-well flat-bottom plates in a final volume of 200 µl in the
presence of the indicated concentrations of Ag. After 48 h,
supernatants were harvested for nitrite determination and cell lysates
prepared for arginase determination. To analyze the expression of
arginase I and iNOS protein in BMM-T cell cocultures by Western
blot, 5 x 106 BMM were cultured together
with 1 x 107 T cells and the respective Ag
in 55 mm Petriperm hydrophob petri dishes (Heraeus) in a final volume
of 5 ml, and cell lysates prepared after 48 h.
SDS-PAGE and Western blot analysis
Cells were stimulated in 55 mm Petriperm hydrophob petri dishes in a final volume of 5 ml. After 48 h, cells were harvested with a rubber policeman, washed twice in PBS, pelleted, and lysed for 30 min on ice in 200 µl of lysis buffer, consisting of 150 mM NaCl, 10 mM Tris-HCl (pH 7.5), and 0.5% Triton X-100. Cell debris was spun down at 13,000 x g for 5 min at 4°C, and protein concentrations of the cleared cellular lysates were determined by the bicinchoninic acid assay (Pierce, Rockford, IL). The samples were mixed 1:1 with sample buffer (125 mM Tris-HCl (pH 6.8), 20% glycerol (v/v), 4% SDS, 40 mM DTT, and 0.01% bromphenol blue), boiled for 5 min, and 20 µg aliquots of protein were separated on a 7.5% (for detection of iNOS) or 12.5% (for detection of arginase) SDS-PAGE gel. The proteins were transferred to a nitrocellulose membrane (Schleicher & Schuell, Keene, NH), which was then blocked with 5% nonfat dry milk in PBS at 4°C overnight. In the case of iNOS detection, the membrane was incubated with a monoclonal anti-iNOS Ab (Transduction Laboratories, Lexington, KY) for 1 h and subsequently with alkaline phosphatase-conjugated goat anti-mouse IgG (Rockland, Gilbertsville, PA) for 1 h. In the case of arginase detection, the membrane was incubated for 1 h with a 1:5000 dilution of a polyclonal rabbit anti-rat arginase I antiserum (18), which is cross-reactive to murine arginase I. The membrane was then incubated with alkaline phosphatase-conjugated goat anti-rabbit Ig (Southern Biotechnology Associates, Birmingham, AL). Finally, the blots were incubated with 5-bromo-4-chloro-3-indolyl-phosphate/nitro blue tetrazolium reagent (Kierkegaard & Perry Laboratories, Gaithersburg, MD) for 10–15 min.
RNA extraction and RT-PCR
Cells (1 x 106) were stimulated in 24-well flat-bottom plates in a final volume of 1 ml. At the indicated time points, total cellular RNA of the cells was prepared with TriReagent (Molecular Research Center, Cincinnati, OH), according to the manufacturer‘s instruction. Reverse transcription was performed at 37°C for 60 min in 30 µl containing 3 µg of total RNA, 0.4 mM of each dNTP and 50 µ pd(N)6 (all from Pharmacia, Freiburg, Germany), 200 U Moloney murine leukemia virus reverse transcriptase, 1 mM DTT (both from Life Technologies), 50 mM Tris-HCl (pH 8.3), 3 mM MgCl2 and 62.5 mM KCl. A total of 0.01–1 µl of the resulting cDNA (adjusted to a concentration of 50 ng/µl input RNA) was then amplified by PCR in a 50 µl reaction mixture containing 0.2 mM of each dNTP, 1 mM DTT, 200 nM of each primer, 0.6 U Taq polymerase (HT Biotechnology, Cambridge, U.K.), 10 mM Tris-HCl (pH 9.0), 1.5 mM MgCl2, 50 mM KCl, 0.01% (w/v) gelatin, and 0.1% Triton X-100. PCR amplification was performed in a DNA thermal cycler (Perkin-Elmer Cetus, Norwalk, CT) for 35 cycles after an initial denaturation step for 5 min at 95°C with the following parameters: 20 s at 95°C, 20 s at 56°C, and 30 s at 72°C. The PCR products were run on a 1.5% agarose gel and stained with ethidium bromide. The sequences for the primers used are: arginase I sense primer, 5'-CAGAAGAATGGAAGAGTCAG-3' and arginase I antisense primer, 5'-CAGATATGCAGGGAGTCACC-3' generating a 250-bp PCR product, arginase II sense primer, 5'-TGATTGGCAAAAGGCAGAGG-3' and arginase II antisense primer, 5'-CTAGGAGTAGGAAGGTGGTC-3' generating a 310-bp PCR product, ß-actin sense primer, 5'-TGGAATCCTGTGGCATCCATGAAAC-3' and ß-actin antisense primer, 5'-TAAAACGCAGCTCAGTAACAGTCCG-3' generating a 348-bp PCR product.
Statistical evaluation
Results were analyzed by ANOVA without repeated measurement correction and by Dunnett’s multiple comparison test.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
by Th2 cytokines
Cytokine-mediated regulation of arginase isoforms in murine BMM
was investigated by RT-PCR with primers that discriminate between
arginase I and II cDNA sequences. The identities of the amplified
products were ensured by DNA sequencing (data not shown). Murine liver
(arginase I) and kidney (arginase II) cDNA preparations were employed
as positive/negative controls. In the experiment depicted in Fig. 1
A, arginase I mRNA was not
detected in unstimulated BMM. In the presence of the Th2 cytokine
IL-4, a prominent induction of arginase I mRNA was observed within
2 h of stimulation. Whereas IL-10 stimulated a far less pronounced
and transient expression of arginase I mRNA, this cytokine efficiently
enhanced the induction of arginase I mRNA by IL-4, confirming the
previously observed synergism between these cytokines as determined by
measuring arginase activity (11). Th1 cytokines did not
induce arginase I mRNA until 24 h of stimulation when a moderate
induction of arginase I mRNA was notable upon stimulation with IFN-
or IFN- + TNF-. Induction of arginase I mRNA by Th1 cytokines did
not take place in BMM of mice in which the IL-10 gene was deleted by
homologous recombination (Fig. 1B), and is therefore
probably a secondary effect of IL-10, secreted by the macrophages upon
Th1 cytokine stimulation. On the other hand, blocking experiments with
a mAb against IL-10, which completely blocked arginase induction by
exogenously added IL-10, solely demonstrated a partial inhibition of
arginase induction (reduction of the 48 h stimulation index of
arginase induction of BMM induced with IFN- + TNF- from 3.1 to
2.1 upon addition of the anti-IL10 mAb, data not shown).
Considering the clear-cut results with the IL-10 KO mice, endogenously
produced IL-10 is probably able to signal rapidly via its receptor
before it can be completely blocked by the Ab.
|
, suggesting that
this isoform is responsible for the background activity of arginase in
resting macrophages. No significant modulation of arginase II mRNA was
seen under all conditions of stimulation at all time points tested. It
should be mentioned that in two of five experiments, a weak signal of
arginase I mRNA was detectable by RT-PCR also in unstimulated BMM.
Minor differences in the preactivation status of the BMM may be
responsible for these slightly varying results (also see below).
Induction of arginase I protein in murine BMM by Th2 cytokines
Selective induction of arginase I on the protein level was
investigated by Western blot analysis, employing a rabbit
anti-arginase I polyclonal antiserum (18). Lysates of
murine liver and kidney served as positive and negative controls,
respectively (Fig. 2A). As
previously shown, the polyclonal antiserum reacts with two polypeptides
of murine hepatic arginase with m.w. of 35 and 38 kDa, presumably
arising by alternative translation initiation (19) or by
posttranscriptional modification (18, 20). Murine BMM
were stimulated with various cytokines for 48 h, cell lysates were
separated by SDS-PAGE and analyzed for iNOS and arginase by Western
Blot (Fig. 2B). Arginase activities were determined in the
same cell lysates, and nitrites were determined in the supernatants of
the cultures at 48 h (before lysate preparation) and are indicated
below each lane. The competitive regulation of the two pathways of
arginine metabolism is demonstrated by the reciprocal induction of
arginase I and iNOS. Th2 cytokines did not induce iNOS activity or
protein but efficiently induced arginase I activity and protein, with a
pronounced synergism between IL-4 and IL-10. The Th1 cytokine IFN-
alone failed to induce arginase or iNOS. IFN- in cooperation with
TNF- caused a pronounced induction of iNOS and only a marginal
induction of arginase. In the experiment in Fig. 2, arginase I protein
was detectable even in unstimulated BMM, which was the case in two
of four independent experiments. Arginase I expression in unstimulated
murine BMM (15–60 mU/106 cells) most probably
reflects unintentional preactivation of the macrophages (see also
above).
|
by Th2 cells
We could recently demonstrate that the iNOS/arginase balance in
macrophages is regulated by Th1 and Th2 cells via Ag-induced secretion
of their corresponding cytokines (11). The isoform of
arginase induced in macrophages by Th2 cells was tested using two
well-defined CD4+ T cell clones, AE7 and D10G4,
which belong to the Th1 and Th2 subsets, respectively. BMM of mouse
strain AKR/N served as APCs and were cocultured together with the T
cell clones and the corresponding Ag at several concentrations. After
48 h, cell lysates were prepared and analyzed by SDS-PAGE and
Western blot analysis for the expression of arginase I and iNOS (Fig. 3). As expected, the Th1 clone induced
nitrites and iNOS protein Ag-dependently, without inducing arginase,
and no induction of iNOS or nitrites by the Th2 cells was detectable.
The Th2 clone D10G4 induced arginase activity, in the presence of Ag to
very high levels, corresponding to a strong induction of arginase I
observed by Western blotting (Fig. 3). As previously reported
(11), this Th2 clone induces considerable levels of
arginase activity when cocultured with the macrophages even without Ag
(here 493 mU/106 cells). As shown in Fig. 3, this
background activity corresponds to the induction of arginase I protein
as well. The induction of arginase I by the Th2 clone was also
confirmed at the level of RNA by RT-PCR (data not shown).
|
In addition to macrophages, dendritic cells represent the second
major class of myeloid professional APCs (21). The
iNOS/arginase balance has so far not been studied in dendritic cells.
BMDC were generated and extensively analyzed phenotypically by flow
cytometry (data not shown) as well as functionally in primary
stimulation cultures with naive T cells (data not shown). The cells
were efficient APCs and showed homogenous expression of CD11c, MAC-1,
F4/80, MHCII, and CD80. However, the cells were heterogenous
(intermediate to high) in the expression of the costimulatory molecules
CD86 and CD40, suggesting that they differed in their state of
maturity. These BMDC, as well as the retrovirally immortalized
dendritic cell line D2SC/1 (17), were analyzed for
expression of iNOS and arginase upon incubation with various Th1 or Th2
cytokines (Fig. 4). In BMDC, a high
resting level of arginase activity in the range of 200–250
mU/106 cells was reproducibly noted. Arginase
activity was increased by the Th2 cytokine IL-4. IL-10, having no
significant effect on its own, cooperated with IL-4 in arginase
induction. In contrast, the Th1 cytokines up-regulated solely iNOS. A
similar pattern of regulation was seen with the dendritic cell line
D2SC/1 (Fig. 4), with the exception that no resting arginase activity
was detectable.
|
). Similar to our earlier findings with
BMM (11), the Th1 clone induced nitrites Ag-dependently
without up-regulating arginase activity (Fig. 5). While no induction of
iNOS was seen in the BMDC/Th2 cocultures, arginase activity was
up-regulated Ag-dependently to very high levels (3000–3200
mU/106 cells). Similar to BMM, the Th2 clone
also caused a significant induction of arginase activity in the BMDC
even without addition of Ag (here: 1750 mU/106
cells). As already discussed in our earlier study (11),
this might be due to cell membrane-bound cytokines or to minimal
amounts of cytokines secreted by not completely resting T cells.
Together, the data show that the two L-arginine
metabolizing enzymes in BMDC are subject to a similar competitive
regulation as in BMM (9, 11).
|
D2SC/1 cells were stimulated with Th1 and Th2 cytokines or LPS.
Cell lysates were prepared to analyze the induction of arginase
isoforms at the level of mRNA (Fig. 6A) and protein (Fig. 6B). In agreement with the data on arginase activity (Fig. 4
), neither arginase I nor arginase II was detected in unstimulated
D2SC/1 cells at RNA and protein level. Similar to macrophages, IL-4 and
IL-13 specifically induced the hepatic isoform of arginase, while no
induction of arginase II (under all conditions of stimulation) was
noted.
|
and more
pronounced by IFN- + TNF- (Fig. 6A), but neither of
these modes of stimulation was reflected by protein induction
detectable by Western blot (Fig. 6B). In contrast to
macrophages (see Fig. 2), stimulation with LPS led to no detectable
induction of arginase activity (see also Fig. 4) or arginase protein,
although a faint signal for arginase I mRNA was detectable. A prominent
finding was again the strong synergism of the Th2 cytokines IL-4 and
IL-10 in the induction of arginase I. |
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Similarly inconsistent results were also reported on the regulation of arginase isoforms in tissues other than macrophages. Arginase I and arginase II were both up-regulated during hyperoxic lung damage in rats (27). LPS caused an induction of arginase I in rat lung and spleen in vivo (19). Another group found the constitutive expression of arginase II in normal rat lung (alveolar + bronchial epithelium, pulmonary macrophages), whereas this expression was lost during sepsis and iNOS expression was induced (28). In a rat model of immune glomerulonephritis, arginase II was detectable in normal glomeruli, whereas nephritic glomeruli expressed both arginase I and arginase II. IL-4 increased urea production in nephritic glomeruli and had no effect on normal glomeruli (29).
No definitive picture so far emerges on the in vivo functions of the arginases in macrophages or other tissues, so that this issue remains for the most part at the level of speculation. Various suggestions for the extrahepatically expressed arginase II have been made (6). Our new observations corroborate our previous suggestion for a minimal function of arginase I in macrophages: the up-regulation in the context of Th2 responses points toward an antiinflammatory role. Because arginase I and iNOS are expressed in the cytosol, arginase I can inhibit iNOS by competing for the common substrate L-arginine (9). Another antiinflammatory function of arginase might be a consequence of its synthesis of L-ornithine, the precursor amino acid for the polyamines putrescine, spermidine, and spermine. Spermine suppresses NO production in macrophages activated with LPS (30) and inhibits specifically the synthesis of proinflammatory cytokines in human mononuclear cells (31).
However, as arginase and iNOS are competitively regulated at the level of gene expression, we do not think that the function of arginase I is restricted to a negative (passive) regulation of iNOS. Rather, it is likely that arginase I plays a positive (active) role in the context of Th2-dominated immune responses. For example, arginase may participate in fibrogenic processes via the synthesis of ornithine-derived proline, an essential precursor for the production of collagen. In a murine model of granulomatous inflammation, it was shown that the tissue-destructing fibrosis of Th2 type granuloma is due to an IL-4-induced synthesis of collagen (32). Additionally, an in vivo model of liver fibrosis showed that BALB/c mice, demonstrating a Th2 cytokine profile, developed massive liver fibrosis, whereas the Th1 cytokine profile of C57BL/6 mice was accompanied by only minimal fibrosis. Neutralization of IL-4 in BALB/c mice resulted in a drastic reduction of fibrosis (33). Arginase might also play a similar role during wound healing. A reciprocal regulation of iNOS and arginase activity was already demonstrated in rats with iNOS up-regulation in the early phase of wound healing, probably creating a cytotoxic environment, and arginase up-regulation in the later, reparative phase (34). The hypoxic environment in healing wounds could be one additional inducer of arginase (23).
While an induction of iNOS in dendritic cells via stimulation with
IFN- ± LPS was already described in the literature (17, 35), we demonstrated in this study for the first time that
dendritic cells express the alternative enzyme arginase. The high
background level of arginase activity in the BMDC is causally unclear,
but is probably induced by the cytokine GM-CSF, which is used for
differentiation of the cells. In BMM, GM-CSF induces arginase
activity in the range of 100–150 mU/106 cells
(data not shown).
Regarding expression of arginase I, a recent paper demonstrated that
the regulation in liver and RAW 264.7 macrophages clearly differs
(25). Whereas arginase I is induced in the liver by
glucocorticoids (36), dexamethasone led to no induction of
arginase I in RAW 264.7 macrophages and even inhibited arginase I
up-regulation induced by LPS (25). Dexamethasone also led
to no arginase induction in our BMM (data not shown). Besides our
previous demonstration of the involvement of protein kinase A in the
induction of arginase in BMM (37), the Th2
cytokine-associated signal transduction pathways and the molecular
events leading to induction of arginase in macrophages and dendritic
cells are largely unknown.
Regarding the level of regulation, the induction of arginase I mRNA
always seemed to account for the increase in detectable protein in the
Western blot and the concomitant increase in measurable arginase
activity. We recently elucidated the strong synergistic induction of
arginase activity in BMM by combinations of Th2 cytokines (most
pronounced between IL-4 and IL-10) as the basis of the very efficient
induction of the enzyme by Th2 cells. Now, we could demonstrate that
this novel synergism is also seen on RNA and protein level.
Nevertheless, further studies are needed to determine whether the
Th2-mediated regulation of arginase expression is solely
transcriptionally or also on translational or posttranslational
levels.
Our findings provide new insights into the complex regulation of this still rather unknown family of enzymes and should help to clarify the functional importance of arginase within the immune system. An intriguing observation of this study is the detection of a further strong element of similarity between the two enzymatic pathways of arginine metabolism in macrophages and dendritic cells: both pathways are mediated by two isoenzymes, one constitutively expressed and the other inducible. Most probably, this reflects different functions fulfilled by the two isoforms in different cell types and subcellular localizations under varying (patho-) physiologic circumstances.
Note added in proof.
Since the submission of this manuscript a study (C. A. Louis, V. Mody, W. L. Henry, Jr., J. S. Reichner, and J. E. Albina. 1999. Regulation of arginase isoforms I and II by IL-4 in cultured murine peritoneal macrophages. Am. J. Physiol. 276:R237) was published that addressed some aspects of the work presented here and demonstrated the selective up-regulation of arginase I in murine peritoneal macrophages.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. Manuel Modolell, Max-Planck-Institut für Immunbiologie, Stübeweg 51, D-79108 Freiburg, Germany. E-mail address:
3 Abbreviations used in this paper: iNOS, inducible NO synthase; BMM, bone marrow-derived macrophages; BMDC, bone marrow-derived dendritic cells; PCC, pigeon cytochrome c.
Received for publication February 2, 1999. Accepted for publication July 26, 1999.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
, endotoxin, amd interaction with allogeneic T cells. J. Immunol. 157:3577.[Abstract]
This article has been cited by other articles:
|
|
 |
|
  M. Ishii, H. Wen, C. A. S. Corsa, T. Liu, A. L. Coelho, R. M. Allen, W. F. Carson IV, K. A. Cavassani, X. Li, N. W. Lukacs, et al. Epigenetic regulation of the alternatively activated macrophage phenotype Blood, October 8, 2009; 114(15): 3244 - 3254. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Zhang, B. Baban, M. Rojas, S. Tofigh, S. K. Virmani, C. Patel, M. A. Behzadian, M. J. Romero, R. W. Caldwell, and R. B. Caldwell Arginase Activity Mediates Retinal Inflammation in Endotoxin-Induced Uveitis Am. J. Pathol., August 1, 2009; 175(2): 891 - 902. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Oberlies, C. Watzl, T. Giese, C. Luckner, P. Kropf, I. Muller, A. D. Ho, and M. Munder Regulation of NK Cell Function by Human Granulocyte Arginase J. Immunol., May 1, 2009; 182(9): 5259 - 5267. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Mise-Omata, E. Kuroda, T. Sugiura, U. Yamashita, Y. Obata, and T. S. Doi The NF-{kappa}B RelA Subunit Confers Resistance to Leishmania major by Inducing Nitric Oxide Synthase 2 and Fas Expression but Not Th1 Differentiation J. Immunol., April 15, 2009; 182(8): 4910 - 4916. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Villalta, H. X. Nguyen, B. Deng, T. Gotoh, and J. G. Tidball Shifts in macrophage phenotypes and macrophage competition for arginine metabolism affect the severity of muscle pathology in muscular dystrophy Hum. Mol. Genet., February 1, 2009; 18(3): 482 - 496. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B.-S. Choi, I. C. Martinez-Falero, C. Corset, M. Munder, M. Modolell, I. Muller, and P. Kropf Differential impact of L-arginine deprivation on the activation and effector functions of T cells and macrophages J. Leukoc. Biol., February 1, 2009; 85(2): 268 - 277. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Siracusa, J. J. Reece, J. F. Urban Jr., and A. L. Scott Dynamics of lung macrophage activation in response to helminth infection J. Leukoc. Biol., December 1, 2008; 84(6): 1422 - 1433. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. A. Shirey, L. E. Cole, A. D. Keegan, and S. N. Vogel Francisella tularensis Live Vaccine Strain Induces Macrophage Alternative Activation as a Survival Mechanism J. Immunol., September 15, 2008; 181(6): 4159 - 4167. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. J. E. Raveney, C. Richards, M.-L. Aknin, D. A. Copland, B. R. Burton, E. Kerr, L. B. Nicholson, N. A. Williams, and A. D. Dick The B Subunit of Escherichia coli Heat-Labile Enterotoxin Inhibits Th1 but Not Th17 Cell Responses in Established Experimental Autoimmune Uveoretinitis Invest. Ophthalmol. Vis. Sci., September 1, 2008; 49(9): 4008 - 4017. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Bryk, J. B. Ochoa, M. I. T. Correia, V. Munera-Seeley, and P. J. Popovic Effect of Citrulline and Glutamine on Nitric Oxide Production in RAW 264.7 Cells in an Arginine-Depleted Environment JPEN J Parenter Enteral Nutr, July 1, 2008; 32(4): 377 - 383. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. S. Murphy, V. Sundareshan, T. J. Cory, D. Hayes Jr, M. I. Anstead, and D. J. Feola Azithromycin alters macrophage phenotype J. Antimicrob. Chemother., March 1, 2008; 61(3): 554 - 560. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. C. MacKinnon, S. L. Farnworth, P. S. Hodkinson, N. C. Henderson, K. M. Atkinson, H. Leffler, U. J. Nilsson, C. Haslett, S. J. Forbes, and T. Sethi Regulation of Alternative Macrophage Activation by Galectin-3 J. Immunol., February 15, 2008; 180(4): 2650 - 2658. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.-S. Chiang, F.-H. Chen, J.-H. Hong, P.-S. Jiang, H.-L. Huang, C.-C. Wang, and W. H. McBride Functional phenotype of macrophages depends on assay procedures Int. Immunol., February 1, 2008; 20(2): 215 - 222. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Kitowska, D. Zakrzewicz, M. Konigshoff, I. Chrobak, F. Grimminger, W. Seeger, P. Bulau, and O. Eickelberg Functional role and species-specific contribution of arginases in pulmonary fibrosis Am J Physiol Lung Cell Mol Physiol, January 1, 2008; 294(1): L34 - L45. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Takemoto, K. Ogino, M. Shibamori, T. Gondo, Y. Hitomi, T. Takigawa, D.-H. Wang, J. Takaki, H. Ichimura, Y. Fujikura, et al. Transiently, paralleled upregulation of arginase and nitric oxide synthase and the effect of both enzymes on the pathology of asthma Am J Physiol Lung Cell Mol Physiol, December 1, 2007; 293(6): L1419 - L1426. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Weng, D. Huntley, I-F. Huang, O. Foye-Jackson, L. Wang, A. Sarkissian, Q. Zhou, W. A. Walker, B. J. Cherayil, and H. N. Shi Alternatively Activated Macrophages in Intestinal Helminth Infection: Effects on Concurrent Bacterial Colitis J. Immunol., October 1, 2007; 179(7): 4721 - 4731. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Chen, C. MacLeod, B. Deng, L. Mason, M. Kasaian, S. Goldman, S. Wolf, C. Williams, and M. R. Bowman CAT-2 amplifies the agonist-evoked force of airway smooth muscle by enhancing spermine-mediated phosphatidylinositol-(4)-phosphate-5-kinase-{gamma} activity Am J Physiol Lung Cell Mol Physiol, October 1, 2007; 293(4): L883 - L891. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Badn, E. Visse, A. Darabi, K. E. Smith, L. G. Salford, and P. Siesjo Postimmunization with IFN-{gamma}-Secreting Glioma Cells Combined with the Inducible Nitric Oxide Synthase Inhibitor Mercaptoethylguanidine Prolongs Survival of Rats with Intracerebral Tumors J. Immunol., September 15, 2007; 179(6): 4231 - 4238. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. E. Talmadge Pathways Mediating the Expansion and Immunosuppressive Activity of Myeloid-Derived Suppressor Cells and Their Relevance to Cancer Therapy Clin. Cancer Res., September 15, 2007; 13(18): 5243 - 5248. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Johann, V. Barra, A.-M. Kuhn, A. Weigert, A. von Knethen, and B. Brune Apoptotic cells induce arginase II in macrophages, thereby attenuating NO production FASEB J, September 1, 2007; 21(11): 2704 - 2712. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. J. S. Rocha, U. Schleicher, J. Mattner, G. Alber, and C. Bogdan Cytokines, Signaling Pathways, and Effector Molecules Required for the Control of Leishmania (Viannia) braziliensis in Mice Infect. Immun., August 1, 2007; 75(8): 3823 - 3832. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Copland, C. J. Calder, B. J.E. Raveney, L. B. Nicholson, J. Phillips, H. Cherwinski, M. Jenmalm, J. D. Sedgwick, and A. D. Dick Monoclonal Antibody-Mediated CD200 Receptor Signaling Suppresses Macrophage Activation and Tissue Damage in Experimental Autoimmune Uveoretinitis Am. J. Pathol., August 1, 2007; 171(2): 580 - 598. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Rodriguez, J. Mages, H. Dietrich, N. Wantia, H. Wagner, R. Lang, and T. Miethke MyD88-dependent changes in the pulmonary transcriptome after infection with Chlamydia pneumoniae Physiol Genomics, July 18, 2007; 30(2): 134 - 145. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Amatucci, T. Novobrantseva, K. Gilbride, M. Brickelmaier, P. Hochman, and A. Ibraghimov Recombinant ST2 boosts hepatic Th2 response in vivo J. Leukoc. Biol., July 1, 2007; 82(1): 124 - 132. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-L. Boulland, J. Marquet, V. Molinier-Frenkel, P. Moller, C. Guiter, F. Lasoudris, C. Copie-Bergman, M. Baia, P. Gaulard, K. Leroy, et al. Human IL4I1 is a secreted L-phenylalanine oxidase expressed by mature dendritic cells that inhibits T-lymphocyte proliferation Blood, July 1, 2007; 110(1): 220 - 227. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Ckless, A. van der Vliet, and Y. Janssen-Heininger Arginase Modulates NF-{kappa}B Activity via a Nitric Oxide-Dependent Mechanism Am. J. Respir. Cell Mol. Biol., June 1, 2007; 36(6): 645 - 653. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. J. Popovic, H. J. Zeh III, and J. B. Ochoa Arginine and Immunity J. Nutr., June 1, 2007; 137(6): 1681S - 1686S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Saidi, G. Magri, C. Carbonneil, N. Nasreddine, M. Requena, and L. Belec IFN-{gamma}-activated monocytes weakly produce HIV-1 but induce the recruitment of HIV-sensitive T cells and enhance the viral production by these recruited T cells J. Leukoc. Biol., March 1, 2007; 81(3): 642 - 653. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. C. Thomas, G. B. Sala-Newby, Y. Ismail, J. L. Johnson, G. Pasterkamp, and A. C. Newby Genomics of Foam Cells and Nonfoamy Macrophages From Rabbits Identifies Arginase-I as a Differential Regulator of Nitric Oxide Production Arterioscler Thromb Vasc Biol, March 1, 2007; 27(3): 571 - 577. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Yang, D. Rangasamy, K. I. Matthaei, A. J. Frew, N. Zimmmermann, S. Mahalingam, D. C. Webb, D. J. Tremethick, P. J. Thompson, S. P. Hogan, et al. Inhibition of Arginase I Activity by RNA Interference Attenuates IL-13-Induced Airways Hyperresponsiveness J. Immunol., October 15, 2006; 177(8): 5595 - 5603. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J. Reece, M. C. Siracusa, and A. L. Scott Innate Immune Responses to Lung-Stage Helminth Infection Induce Alternatively Activated Alveolar Macrophages Infect. Immun., September 1, 2006; 74(9): 4970 - 4981. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Moran, R. A. Gonzalez-Polo, G. Soler, and J. M. Fuentes Th1/Th2 Cytokines: An Easy Model to Study Gene Expression in Immune Cells CBE Life Sci Educ, September 1, 2006; 5(3): 287 - 295. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Munder, H. Schneider, C. Luckner, T. Giese, C.-D. Langhans, J. M. Fuentes, P. Kropf, I. Mueller, A. Kolb, M. Modolell, et al. Suppression of T-cell functions by human granulocyte arginase Blood, September 1, 2006; 108(5): 1627 - 1634. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Hassanzadeh Ghassabeh, P. De Baetselier, L. Brys, W. Noel, J. A. Van Ginderachter, S. Meerschaut, A. Beschin, F. Brombacher, and G. Raes Identification of a common gene signature for type II cytokine-associated myeloid cells elicited in vivo in different pathologic conditions Blood, July 15, 2006; 108(2): 575 - 583. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Yeramian, L. Martin, N. Serrat, L. Arpa, C. Soler, J. Bertran, C. McLeod, M. Palacin, M. Modolell, J. Lloberas, et al. Arginine Transport via Cationic Amino Acid Transporter 2 Plays a Critical Regulatory Role in Classical or Alternative Activation of Macrophages J. Immunol., May 15, 2006; 176(10): 5918 - 5924. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Martin, M. Comalada, L. Marti, E. I. Closs, C. L. MacLeod, R. Martin del Rio, A. Zorzano, M. Modolell, A. Celada, M. Palacin, et al. Granulocyte-macrophage colony-stimulating factor increases L-arginine transport through the induction of CAT2 in bone marrow-derived macrophages Am J Physiol Cell Physiol, May 1, 2006; 290(5): C1364 - C1372. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Erdely, D. Kepka-Lenhart, M. Clark, P. Zeidler-Erdely, M. Poljakovic, W. J. Calhoun, and S. M. Morris Jr Inhibition of phosphodiesterase 4 amplifies cytokine-dependent induction of arginase in macrophages Am J Physiol Lung Cell Mol Physiol, March 1, 2006; 290(3): L534 - L539. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. S. Getz and C. A. Reardon Arginine/Arginase NO NO NO Arterioscler Thromb Vasc Biol, February 1, 2006; 26(2): 237 - 239. [Full Text] [PDF]
|
|
|
|
|
|
J. L. M. Wanderley, M. E. C. Moreira, A. Benjamin, A. C. Bonomo, and M. A. Barcinski Mimicry of Apoptotic Cells by Exposing Phosphatidylserine Participates in the Establishment of Amastigotes of Leishmania (L) amazonensis in Mammalian Hosts J. Immunol., February 1, 2006; 176(3): 1834 - 1839. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Holscher, B. Arendse, A. Schwegmann, E. Myburgh, and F. Brombacher Impairment of Alternative Macrophage Activation Delays Cutaneous Leishmaniasis in Nonhealing BALB/c Mice J. Immunol., January 15, 2006; 176(2): 1115 - 1121. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. C. Rodriguez, C. P. Hernandez, D. Quiceno, S. M. Dubinett, J. Zabaleta, J. B. Ochoa, J. Gilbert, and A. C. Ochoa Arginase I in myeloid suppressor cells is induced by COX-2 in lung carcinoma J. Exp. Med., October 3, 2005; 202(7): 931 - 939. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Rehli{section}, S. Sulzbacher, S. Pape, T. Ravasi, C. A. Wells, S. Heinz, L. Sollner, C. El Chartouni, S. W. Krause, E. Steingrimsson, et al. Transcription Factor Tfec Contributes to the IL-4-Inducible Expression of a Small Group of Genes in Mouse Macrophages Including the Granulocyte Colony-Stimulating Factor Receptor J. Immunol., June 1, 2005; 174(11): 7111 - 7122. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Arora, Y. Hernandez, J. R. Erb-Downward, R. A. McDonald, G. B. Toews, and G. B. Huffnagle Role of IFN-{gamma} in Regulating T2 Immunity and the Development of Alternatively Activated Macrophages during Allergic Bronchopulmonary Mycosis J. Immunol., May 15, 2005; 174(10): 6346 - 6356. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Hostetter, E. Huffman, K. Byl, and E. Steadham Inducible Nitric Oxide Synthase Immunoreactivity in the Granulomatous Intestinal Lesions of Naturally Occurring Bovine Johne's Disease Vet. Pathol., May 1, 2005; 42(3): 241 - 249. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Munder, F. Mollinedo, J. Calafat, J. Canchado, C. Gil-Lamaignere, J. M. Fuentes, C. Luckner, G. Doschko, G. Soler, K. Eichmann, et al. Arginase I is constitutively expressed in human granulocytes and participates in fungicidal activity Blood, March 15, 2005; 105(6): 2549 - 2556. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-K. Peng, J.-S. Lin, J. T. Kung, F. D. Finkelman, and B. A. Wu-Hsieh The combined effect of IL-4 and IL-10 suppresses the generation of, but does not change the polarity of, type-1 T cells in Histoplasma infection Int. Immunol., February 1, 2005; 17(2): 193 - 205. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Sinha, V. K. Clements, and S. Ostrand-Rosenberg Reduction of Myeloid-Derived Suppressor Cells and Induction of M1 Macrophages Facilitate the Rejection of Established Metastatic Disease J. Immunol., January 15, 2005; 174(2): 636 - 645. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Donnelly, S. M. O'Neill, M. Sekiya, G. Mulcahy, and J. P. Dalton Thioredoxin Peroxidase Secreted by Fasciola hepatica Induces the Alternative Activation of Macrophages Infect. Immun., January 1, 2005; 73(1): 166 - 173. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Kwong, R. A. Vaishnav, Y. Liu, N. Subhedar, A. J. Stromberg, M. L. Getchell, and T. V. Getchell Target ablation-induced regulation of macrophage recruitment into the olfactory epithelium of Mip-1{alpha}-/- mice and restoration of function by exogenous MIP-1{alpha} Physiol Genomics, December 15, 2004; 20(1): 73 - 86. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Andersson, R. Kokkola, J. Wefer, H. Erlandsson-Harris, and R. A. Harris Differential macrophage expression of IL-12 and IL-23 upon innate immune activation defines rat autoimmune susceptibility J. Leukoc. Biol., December 1, 2004; 76(6): 1118 - 1124. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Kaviratne, M. Hesse, M. Leusink, A. W. Cheever, S. J. Davies, J. H. McKerrow, L. M. Wakefield, J. J. Letterio, and T. A. Wynn IL-13 Activates a Mechanism of Tissue Fibrosis That Is Completely TGF-{beta} Independent J. Immunol., September 15, 2004; 173(6): 4020 - 4029. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. P. Gobert, Y. Cheng, M. Akhtar, B. D. Mersey, D. R. Blumberg, R. K. Cross, R. Chaturvedi, C. B. Drachenberg, J.-L. Boucher, A. Hacker, et al. Protective Role of Arginase in a Mouse Model of Colitis J. Immunol., August 1, 2004; 173(3): 2109 - 2117. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. R. Morris, M. Poljakovic, L. Lavrisha, L. Machado, F. A. Kuypers, and S. M. Morris Jr. Decreased Arginine Bioavailability and Increased Serum Arginase Activity in Asthma Am. J. Respir. Crit. Care Med., July 15, 2004; 170(2): 148 - 153. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A.-L. Pauleau, R. Rutschman, R. Lang, A. Pernis, S. S. Watowich, and P. J. Murray Enhancer-Mediated Control of Macrophage-Specific Arginase I Expression J. Immunol., June 15, 2004; 172(12): 7565 - 7573. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Kropf, M. A. Freudenberg, M. Modolell, H. P. Price, S. Herath, S. Antoniazi, C. Galanos, D. F. Smith, and I. Muller Toll-Like Receptor 4 Contributes to Efficient Control of Infection with the Protozoan Parasite Leishmania major Infect. Immun., April 1, 2004; 72(4): 1920 - 1928. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. C. Gavrilescu, B. A. Butcher, L. Del Rio, G. A. Taylor, and E. Y. Denkers STAT1 Is Essential for Antimicrobial Effector Function but Dispensable for Gamma Interferon Production during Toxoplasma gondii Infection Infect. Immun., March 1, 2004; 72(3): 1257 - 1264. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. El-Gayar, H. Thuring-Nahler, J. Pfeilschifter, M. Rollinghoff, and C. Bogdan Translational Control of Inducible Nitric Oxide Synthase by IL-13 and Arginine Availability in Inflammatory Macrophages J. Immunol., November 1, 2003; 171(9): 4561 - 4568. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. G. Sandler, M. M. Mentink-Kane, A. W. Cheever, and T. A. Wynn Global Gene Expression Profiles During Acute Pathogen-Induced Pulmonary Inflammation Reveal Divergent Roles for Th1 and Th2 Responses in Tissue Repair J. Immunol., October 1, 2003; 171(7): 3655 - 3667. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. C. Rodriguez, A. H. Zea, J. DeSalvo, K. S. Culotta, J. Zabaleta, D. G. Quiceno, J. B. Ochoa, and A. C. Ochoa L-Arginine Consumption by Macrophages Modulates the Expression of CD3{zeta} Chain in T Lymphocytes J. Immunol., August 1, 2003; 171(3): 1232 - 1239. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Martinez-Pomares, D. M. Reid, G. D. Brown, P. R. Taylor, R. J. Stillion, S. A. Linehan, S. Zamze, S. Gordon, and S. Y. C. Wong Analysis of mannose receptor regulation by IL-4, IL-10, and proteolytic processing using novel monoclonal antibodies J. Leukoc. Biol., May 1, 2003; 73(5): 604 - 613. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Bronte, P. Serafini, C. De Santo, I. Marigo, V. Tosello, A. Mazzoni, D. M. Segal, C. Staib, M. Lowel, G. Sutter, et al. IL-4-Induced Arginase 1 Suppresses Alloreactive T Cells in Tumor-Bearing Mice J. Immunol., January 1, 2003; 170(1): 270 - 278. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Bruch-Gerharz, O. Schnorr, C. Suschek, K.-F. Beck, J. Pfeilschifter, T. Ruzicka, and V. Kolb-Bachofen Arginase 1 Overexpression in Psoriasis: Limitation of Inducible Nitric Oxide Synthase Activity as a Molecular Mechanism for Keratinocyte Hyperproliferation Am. J. Pathol., January 1, 2003; 162(1): 203 - 211. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. S. Welch, L. Escoubet-Lozach, D. B. Sykes, K. Liddiard, D. R. Greaves, and C. K. Glass TH2 Cytokines and Allergic Challenge Induce Ym1 Expression in Macrophages by a STAT6-dependent Mechanism J. Biol. Chem., November 1, 2002; 277(45): 42821 - 42829. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Stempin, L. Giordanengo, S. Gea, and F. Cerban Alternative activation and increase of Trypanosoma cruzi survival in murine macrophages stimulated by cruzipain, a parasite antigen J. Leukoc. Biol., October 1, 2002; 72(4): 727 - 734. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Lang, D. Patel, J. J. Morris, R. L. Rutschman, and P. J. Murray Shaping Gene Expression in Activated and Resting Primary Macrophages by IL-10 J. Immunol., September 1, 2002; 169(5): 2253 - 2263. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Huang, F. J. DeGraves, S. D. Lenz, D. Gao, P. Feng, D. Li, T. Schlapp, and B. Kaltenboeck The quantity of nitric oxide released by macrophages regulates Chlamydia-induced disease PNAS, March 19, 2002; 99(6): 3914 - 3919. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. C. Morrison and P. H. Correll Activation of the Stem Cell-Derived Tyrosine Kinase/RON Receptor Tyrosine Kinase by Macrophage-Stimulating Protein Results in the Induction of Arginase Activity in Murine Peritoneal Macrophages J. Immunol., January 15, 2002; 168(2): 853 - 860. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. A. Patton, A. C. La Flamme, J. A. Pedras-Vasoncelos, and E. J. Pearce Central Role for Interleukin-4 in Regulating Nitric Oxide-Mediated Inhibition of T-Cell Proliferation and Gamma Interferon Production in Schistosomiasis Infect. Immun., January 1, 2002; 70(1): 177 - 184. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Ravasi, C. Wells, A. Forest, D. M. Underhill, B. J. Wainwright, A. Aderem, S. Grimmond, and D. A. Hume Generation of Diversity in the Innate Immune System: Macrophage Heterogeneity Arises from Gene-Autonomous Transcriptional Probability of Individual Inducible Genes J. Immunol., January 1, 2002; 168(1): 44 - 50. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Hesse, M. Modolell, A. C. La Flamme, M. Schito, J. M. Fuentes, A. W. Cheever, E. J. Pearce, and T. A. Wynn Differential Regulation of Nitric Oxide Synthase-2 and Arginase-1 by Type 1/Type 2 Cytokines In Vivo: Granulomatous Pathology Is Shaped by the Pattern of L-Arginine Metabolism J. Immunol., December 1, 2001; 167(11): 6533 - 6544. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Dickie, A. Roberts, and R. Lee A defect in HIV-1 transgenic murine macrophages results in deficient nitric oxide production J. Leukoc. Biol., October 1, 2001; 70(4): 592 - 600. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. C. Gavrilescu and E. Y. Denkers IFN-{{gamma}} Overproduction and High Level Apoptosis Are Associated with High but Not Low Virulence Toxoplasma gondii Infection J. Immunol., July 15, 2001; 167(2): 902 - 909. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Namangala, P. De Baetselier, W. Noël, L. Brys, and A. Beschin Alternative versus classical macrophage activation during experimental African trypanosomosis J. Leukoc. Biol., March 1, 2001; 69(3): 387 - 396. [Abstract] [Full Text]
|
|
|
|
|
|
R. Rutschman, R. Lang, M. Hesse, J. N. Ihle, T. A. Wynn, and P. J. Murray Cutting Edge: Stat6-Dependent Substrate Depletion Regulates Nitric Oxide Production J. Immunol., February 15, 2001; 166(4): 2173 - 2177. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. P. Gobert, S. Daulouede, M. Lepoivre, J. L. Boucher, B. Bouteille, A. Buguet, R. Cespuglio, B. Veyret, and P. Vincendeau L-Arginine Availability Modulates Local Nitric Oxide Production and Parasite Killing in Experimental Trypanosomiasis Infect. Immun., August 1, 2000; 68(8): 4653 - 4657. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. D. Mills, K. Kincaid, J. M. Alt, M. J. Heilman, and A. M. Hill M-1/M-2 Macrophages and the Th1/Th2 Paradigm J. Immunol., June 15, 2000; 164(12): 6166 - 6173. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
, No cytokine added; IL-4, IL-10, and IL-13, 10
U/ml; LPS, 0.1 µg/ml; IFN-
