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CUTTING EDGE |
Departments of
*
Infectious Diseases and
Biochemistry and Howard Hughes Medical Institute, St. Jude Children’s Research Hospital, Memphis, TN 38105; and
Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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by IL-4 or IL-13 was dependent on Stat6, cell density in the
cultures, and pretreatment for at least 6 h. IL-4/IL-13 did not
interfere with the expression or activity of iNOS but up-regulated
arginase I (the liver isoform of arginase) in a Stat6-dependent manner.
Addition of exogenous arginine completely restored NO production in
IL-4-treated macrophages. Furthermore, impaired killing of the
intracellular pathogen Toxoplasma gondii in IL-4-treated
macrophages was overcome by supplementing L-arginine. The
simple system of regulated substrate competition between arginase and
iNOS has implications for understanding the physiological regulation of
NO production. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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-regulated IFN regulatory factor (IRF) 1 binding to the
iNOS promoter synergistically acting with NF-
B (4, 5, 6)
and regulation of mRNA stability, translation, protein stability,
substrate availability, and the activity of NO scavengers (1, 3) or endogenous enzyme inhibitors (7). In contrast
to the well-understood pathways of iNOS production, our understanding
of how NO levels are reduced, inhibited, or removed are limited.
Three major classes of cytokines have been shown to play roles in
negative regulation of NO production from activated macrophages. IL-10
is a relatively weak inhibitor of iNOS levels while TGF-
negatively
regulates iNOS levels through multiple mechanisms (8).
Studies from mice lacking IL-10 or TGF-1 have shown that both
cytokines play essential, but differing, roles in negative regulation
of iNOS (9, 10). The third class includes IL-4 and IL-13,
related cytokines that are powerful inhibitors of NO production from
activated macrophages (11, 12, 13, 14). IL-4 and IL-13 are
pleiotropic cytokines that play major roles in the regulation of T and
B cell function as well as controlling macrophage activity
(15). Because of the essential role of NO in antimicrobial
immunity, we were interested in determining the molecular explanation
for the inhibitory actions of IL-4/IL-13. Here, we present our
conclusions to this question and identify IL-4/IL-13 as down-regulating
NO by substrate depletion though Stat6-dependent production of
arginase.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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Stat6-deficient mice have been described previously
(16) and were bred in the St. Jude Animal Resources
Center. Control mice (129 xC57BL/6)F2) were
derived from littermates of interbred Stat6 +/-
mice or were purchased from The Jackson Laboratory (no.100903; Bar
Harbor, ME). Mice were age (6–10 wk) and sex matched for experimental
use. Suppressor of cytokine signaling-1 (SOCS1)
-/-, IFN--/- mice
were bred at St. Jude by intercrossing SOCS1+/-,
IFN--/- mice. All procedures were performed
in accordance with institutional guidelines for the care and handling
of experimental animals.
Macrophage isolation and cell culture
Peritoneal-derived macrophages (PDMs) were isolated from the
peritoneal cavities of mice injected with 3 ml Brewer’s thioglycolate
3 days before harvest. Residual erythrocytes were removed with red cell
lysis buffer (Sigma, St. Louis, MO) and plated as described in each
figure legend. Bone marrow-derived macrophages (BMDMs) were obtained by
flushing bone cavities and isolating macrophages by differentiation in
using L cell-conditioned medium as a source of CSF-1. Cells were plated
to the densities described in each figure legend. Adherent macrophages
were used 4–6 days after plating. For most experiments, IL-4 and IL-13
were used at a final concentration of 50 ng/ml, and LPS and IFN-
were used at a final concentrations of 100 and 2 ng/ml,
respectively.
Reagents
Murine IL-4 was obtained from PeproTech (Rocky Hill, NJ). Murine
IL-13 was obtained from R&D Systems (Minneapolis, MN). Recombinant
murine IFN- was made in Escherichia coli (P. J.
Murray, unpublished observations) and contained endotoxin levels <0.06
endotoxin units/ml and was fully functional by titration against a
commercially available standard. E. coli LPS was purchased
from Sigma (St. Louis, MO). Cytokine stocks were made to 1 µg/ml in
complete RPMI 1640 medium. Griess and arginase assay reagents and
cycloheximide were all obtained from Sigma. Rabbit polyclonal
anti-Stat6 Abs were a gift from Dr. Demin Wang (St. Jude),
anti-iNOS Abs were purchased from Biomol (Plymouth Meeting, PA),
anti-Grb2 Abs were obtained from Transduction Laboratories
(Lexington, KY), anti-phospho-Stat1 Abs were obtained from New
England Biolabs (Beverly, MA), and anti-Stat1 Abs (sc-346, E23) and
anti-IRF-1 Abs (sc-640, M20) were purchased from Santa Cruz (Santa
Cruz, CA). The SOCS1 cDNA probe was a gift from Evan Parganas (St.
Jude). A mouse arginase I probe was isolated from IMAGE EST 492949
(GenBank accession number AA097468).
Enzyme assays
Griess assays were performed as described elsewhere (17). Arginase assays were performed using the method of Corraliza et al. (18). iNOS enzyme assays were performed as described by Stuehr (19).
Immunoblotting and immunoprecipitations
Immunoblotting was performed as described previously (9). Pulse radiolabeling of iNOS was performed as described elsewhere (20) using 0.2 mCi/ml [35S]methionine/cysteine (ICN Pharmaceuticals, Los Angeles, CA). Cell lysates were made in radioimmunoprecipitation assay buffer with the addition of protease inhibitors and immunoprecipitated for 3 h at 4°C. Immunoprecipitates were collected with protein A-Sepharose and separated by electrophoresis on 4–15% gradient gels. Gels were fixed in 10% acetic acid and soaked in 2 M sodium salicylate, dried, and exposed to film for 15 h at -80°C.
In vitro infections
PDMs were harvested from C57BL/6 mice injected 5 days previously
with 3% Brewer’s thioglycolate. Cells were adjusted to 8 x
106 cells/ml in complete RPMI 1640 and plated at
50 or 250 µl/well in 96- or 24-well plates, respectively. After
4 h, nonadherent cells were washed away with ice-cold PBS and
adherent cells allowed to recover in complete medium for 1 h.
Cells were incubated with IL-4 (50 ng/ml) for 16 h. LPS and/or
IFN- was added to some wells and then infected with T.
gondii parasites (0.2 parasites/macrophage) for 24 h and then
pulsed with [3H]uracil (1 µCi/well), which is
preferentially incorporated into parasites. Cultures were treated with
or without exogenous arginine and parasite replication was measured by
scintillation counting.
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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chain in their receptor
complexes and both cytokines activate Stat6, which mediates a subset of
their functions in T and B cells (16, 21, 22, 23) and has
previously been shown to be required for inhibiting iNOS mRNA
production in LPS- and IFN--activated macrophages (24).
Our experimental system uses two populations of primary macrophages;
thioglycolate-elicited peritoneal inflammatory macrophages (PDMs) and
in vitro differentiated BMDMs. To test whether Stat6 was required for
IL-4/IL-13 inhibition of NO production, we stimulated macrophages with
IL-4 or IL-13 for 16 h and then treated them with LPS/IFN- for
another 16 h and measured NO with the Griess reaction
(19). This assay detects nitrites as byproducts of NO
generation in the culture supernatants (Fig. 1
A). Both IL-4 and IL-13
inhibited NO from activated PDMs (Fig. 1A) and BMDMs (data
not shown) in a Stat6-dependent manner. In these assays, macrophages
must be pretreated with IL-4/IL-13 to observe NO inhibition. To test
the dependence on time, we pretreated macrophages with IL-4 for
different times before LPS/IFN- treatment (Fig. 1B). The
results show that macrophages must be treated for 
10 h in order for
IL-4 to block NO completely (Fig. 1B). The time dependence
of the effect is important for the interpretation of the experiments
presented below. We also noted that the effects of IL-4 and IL-13 are
highly dependent on the number of macrophages in the culture. To
illustrate this, PDMs were plated at 1.25 x
105-7.5 x 105
cells/well in 24-well plates (Fig. 1C). IL-4 did not inhibit
NO at 1.25 x 105 and 2.5 x
105 cells/well, while >90% inhibition was
observed at 7.5 x 105 cells/well. Similar
findings were observed with BMDMs (data not shown). The inhibition of
NO production by IL-4/IL-13 was not due to the production of a molecule
or substance that interfered with the Griess reaction and was also not
due to the production of a Stat6-regulated soluble factor(s) as shown
by transferring culture supernatants in the presence of neutralizing
anti-IL-4 mAbs (data not shown).
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signaling, iNOS
gene transcription and other mechanisms as being involved in IL-4
inhibition of NO production (11, 12, 24, 25). To test
whether iNOS protein levels were reduced by IL-4/IL-13, we performed
time course experiments to measure the accumulation of iNOS by
immunoblotting. Both IL-4 and IL-13 inhibited NO production but iNOS
levels were unchanged in either case (data not shown). IL-4/IL-13 also
did not inhibit Stat1 phosphorylation or IRF-1
up-regulation when macrophages were stimulated with LPS/IFN-, both
prerequisites for high-level iNOS production, ruling out a role for
IL-4/IL-13 inhibiting these signaling pathways under these
conditions (data not shown). Minor inhibition of Stat1
phosphorylation was observed when macrophages were
stimulated with IL-4 and IFN-; however, this did not appear to
inhibit IRF-1 or iNOS induction. Interestingly, IL-4 did inhibit the
LPS-mediated induction of iNOS, indicating that IL-4 may activate
alternate pathways that can reduce iNOS protein levels (data not
shown). We also tested whether IL-4 regulated newly synthesized iNOS
protein by pulse labeling and immunoprecipitation analysis.
Again, these results failed to reveal any effect of IL-4 on iNOS
synthesis (data not shown). We also tested whether the activity of iNOS
enzyme was affected in macrophages treated with IL-4 and then
LPS/IFN-. Cell-free extracts were used to measure iNOS enzyme
activity using a method established by Stuehr (19). Under
these conditions, we found that iNOS activity was equivalent in lysates
that had been previously treated with IL-4 and LPS/IFN- or
LPS/IFN- alone, even though samples that had been pretreated with
IL-4 showed complete inhibition of NO production (data not shown).
Finally, since we had observed that IL-4 induces expression of SOCS1, a
protein inhibitor of IFN- signaling, the role of SOCS1 was also
tested. Using Northern blotting to check for SOCS1 expression and
SOCS1-/- macrophages, we failed to implicate
this molecule in IL-4-mediated inhibition of NO production (data not
shown). In summary, the results indicate that IL-4/IL-13 regulates NO
production using a molecular mechanism distinct from inhibiting iNOS
levels.
Previous studies have shown that arginase levels can be up-regulated in
macrophages treated with IL-4 or IL-13 (26, 27). This has
been postulated to be a mechanism where IL-4/IL-13-secreting Th2 T
cells direct macrophages to make arginase. In contrast, Th1 T cells
would direct iNOS production via IFN- (26, 27).
However, this hypothesis has not been directly tested in a situation
where macrophages are exposed to both IL-4 and IFN-. We first asked
whether IL-4 controls arginase levels in a Stat6-dependent manner using
a standard arginase assay (18). The results (Fig. 2A) show that indeed, arginase
levels increase substantially following IL-4 treatment, independent of
LPS/IFN- treatment. The increase in arginase levels was strictly
dependent on Stat6 as well as cell density in the cultures. Therefore,
a simple explanation for the data presented in Fig. 1
is that IL-4
up-regulates arginase which then depletes arginine from the cultures.
The greater the cell density, the more arginine would be consumed,
accounting for the cell density dependence of the effect (Fig. 1C). If this scenario was true, then replenishment of
arginine levels in the cultures should restore NO production in cells
treated with IL-4 and then LPS and IFN-. To test this, macrophages
were treated with IL-4 and then LPS/IFN- with additional arginine (2
mM) added to the culture medium. Arginine addition completely rescued
NO production, independent of arginase activity (Fig. 2B).
Therefore, the simplest explanation of the data is that IL-4/IL-13
stimulates arginase activity that depletes arginine levels, leaving
none available for iNOS to generate NO. This is reversible by the
addition of exogenous arginine, providing sufficient substrate for both
iNOS and arginase. iNOS has a significant
Km advantage over arginase I for
arginine, leading to the concept that iNOS would preferentially retain
access to substrate (28, 29). Our data support and extend
this idea since we were able to show that as long as arginine is
present, iNOS is active, whether or not arginase is also actively
consuming substrate. However, if arginase has been induced by
Il-4/IL-13 before iNOS induction and substrate becomes limiting, no NO
will be made by iNOS.
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C). A previous report claimed
six potential Stat6 binding sites are present in the rat arginase I
promoter (30) but our own analysis of this promoter failed
to reveal any sites correlating with the Stat6 consensus binding site
(TTCC(A > T,N)GGAA; Ref. 31). There was a single site
conforming to a potential Stat6 binding site (TTCNNNNGAA; Ref.
32); however, our observations showing that intermediate
proteins are required downstream of Stat6 to regulate arginase I
expression suggests that this site is unlikely to be physiologically
relevant in the regulation of arginase I by IL-4. Finally, the Northern
blot data reveal that 6 h are required to observe significant
arginase I mRNA levels, correlating with the time-dependent requirement
for IL-4 pretreatment of macrophages (Fig. 1).
Since arginase and iNOS compete for arginine, we predicted that the
depletion of substrate would play a significant role in
macrophage-mediated immune mechanisms where NO is important. Therefore,
we tested this concept in an in vitro T. gondii killing
assay (Fig. 3). In this assay, macrophage
anti-toxoplasma activity is dependent upon NO generation
(33). IL-4 pretreatment significantly inhibited
LPS/IFN- killing of T. gondii, while no parasite
replication was detected when macrophages were treated with
LPS/IFN-. Strikingly, addition of exogenous arginine restored
complete killing of T. gondii in the IL-4-treated
macrophages, suggesting that as long as substrate is available to iNOS
the enzyme will actively generate NO (Fig. 3).
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Acknowledgments |
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-/- mice; Evan Parganas for analysis of the rat
arginase I promoter and the SOCS1 cDNA probe; and Demin Wang for
anti-Stat6 Abs. |
Footnotes |
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2 R.R. and R.L. contributed equally to this study.
3 Address correspondence and reprint requests to Dr. Peter J. Murray, Department of Infectious Diseases, St. Jude Children’s Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105.
4 Abbreviations used in this paper: iNOS, inducible NO synthase; PDM, peritoneal-derived macrophage; BMDM, bone marrow-derived macrophage; IRF, IFN regulatory factor.
Received for publication October 30, 2000. Accepted for publication December 19, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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B/Rel in induction of nitric oxide synthase. J. Biol. Chem. 269:4705.. J. Exp. Med. 178:605.1 null mouse. J. Exp. Med. 183:2337.. Eur. J. Immunol. 24:1441.[Medline]
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M. Rodriguez-Sosa, J. R. David, R. Bojalil, A. R. Satoskar, and L. I. Terrazas Cutting Edge: Susceptibility to the Larval Stage of the Helminth Parasite Taenia crassiceps Is Mediated by Th2 Response Induced Via STAT6 Signaling J. Immunol., April 1, 2002; 168(7): 3135 - 3139. [Abstract] [Full Text] [PDF]
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R. Lang, R. L. Rutschman, D. R. Greaves, and P. J. Murray Autocrine Deactivation of Macrophages in Transgenic Mice Constitutively Overexpressing IL-10 Under Control of the Human CD68 Promoter J. Immunol., April 1, 2002; 168(7): 3402 - 3411. [Abstract] [Full Text] [PDF]
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 Y. Murata, T. Shimamura, and J. Hamuro The polarization of Th1/Th2 balance is dependent on the intracellular thiol redox status of macrophages due to the distinctive cytokine production Int. Immunol., February 1, 2002; 14(2): 201 - 212. [Abstract] [Full Text] [PDF]
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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]
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