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and IL-10 Formation by Human Macrophages Is Differentially Regulated at the Level of Mitogen-Activated Protein Kinase Activity1
Departments of
*
Immunochemistry and Biochemical Microbiology and
Immunology and Cell Biology, Research Center Borstel, Borstel, Germany
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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production induced by M. avium
was inhibited by anti-CD14 mAbs, but not by Abs against the
macrophage mannose receptor. Analysis of mitogen-activated protein
(MAP) kinase activation (extracellular signal-regulated kinase 1/2,
p38, and c-Jun NH2-terminal kinase) showed a rapid
phosphorylation of all three subfamilies in response to M.
avium, which was inhibited by anti-CD14 Abs. Using highly
specific inhibitors of p38 (SB203580) and MAP kinase kinase-1
(PD98059), we found that activation of the extracellular
signal-regulated kinase pathway, but not of p38, was essential for the
M. avium-induced TNF- formation. In contrast, IL-10
production was abrogated by the p38 inhibitor, but not by the MAP
kinase kinase-1 inhibitor. In conclusion, M.
avium-induced secretion of TNF- and IL-10 by human
macrophages is differentially regulated at the level of MAP kinase
activity. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Upon initial contact of macrophages with M. avium, a variety
of cellular reactions are triggered, including the production of
reactive oxygen and nitrogen intermediates and the release of
proinflammatory cytokines (e.g., TNF- and IL-6) (reviewed in Ref.
5) as well as anti-inflammatory cytokines (IL-10 and
TGF-
) (6, 7). In vivo, mycobacteria-induced production
of TNF- correlates with accelerated granuloma formation, resulting
in rapid containment of the infectious focus (8). In
contrast, endogenous IL-10 may down-modulate the antimycobacterial
response, as treatment with anti-IL-10 Abs or infection in
IL-10-deficient mice leads to increased clearance of some mycobacterial
strains (6, 9).
Intracellular pathogens such as mycobacteria select specific host cell receptors to facilitate both adherence and entry, including complement receptor types 1, 3, and 4, surfactant receptors, scavenger receptors, and some integrins (reviewed in Ref. 10). In addition, the mannose receptor plays a prominent part in early internalization and processing of mycobacteria (11), although signaling via the macrophage mannose receptor (MMR)3 has not been conclusively demonstrated. Similarly, CD14 is clearly involved in the response to lipoarabinomannan derived from mycobacteria (12). Whether intact mycobacterial cells use CD14 to initiate cytokine production by macrophages has not been determined to date.
Mitogen-activated protein (MAP) kinases are ubiquitous serine/threonine
protein kinases involved in signal transduction in eukaryotic
organisms. Their activity is important for a panoply of cellular
functions, ranging from proliferative to differentiative events and
programmed cell death (13). At least three distinct
families of MAP kinases exist in mammalian cells: the p42/44
extracellular signal-regulated kinase (ERK) MAP kinase, c-Jun
NH2-terminal kinases (JNKs), and p38 MAP kinase.
All three can be activated independently and simultaneously. Whereas
ERK1 and -2 are mainly activated by growth factors or phorbol esters,
JNK and p38 are activated by inflammatory cytokines or cellular
stresses such as osmotic changes and UV light (14).
Bacterial LPS leads to a rapid activation of all three MAP kinase
families (15, 16, 17). Whereas p38 and ERK are of critical
importance for the release of proinflammatory cytokines such as TNF-
and IL-1 (18), only activated p38, but not ERK, is
necessary for IL-10 formation in response to LPS (19).
Whether MAP kinases are involved in TNF- and IL-10 secretion by
human macrophages in response to viable mycobacteria has not been
explored in any detail. In this in vitro study we investigated the role
of two putative surface receptors for mycobacteria, CD14 and MMR, and
made use of selective MAP kinase inhibitors to determine the relative
importance of MAP kinases p38 and ERK-1 in signaling TNF- and IL-10
secretion in response to infection with M. avium.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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M. avium strains SE01 and 2151 SmO were initially derived from AIDS patients (20, 21). Both strains were cultured in Middlebrook 7H9 medium supplemented with oleic acid, albumin, dextrose, and catalase (BD Biosciences, Heidelberg, Germany) to the mid logarithmic phase. Aliquots were frozen at -70°C until needed. For stimulation experiments M. avium strains were thawed at room temperature and spun down with 2000 rpm (830 x g for 10 min). Pellets were resuspended in PBS and added to the cells for the times indicated. To rule out the presence of LPS in the assays, both strains were tested in a Limulus amebocyte lysate assay (BioWhittaker, Walkersville, MD). The effective LPS concentration in the experiments when ratios of 10:1 were used was <2 pg/ml.
Bacterial LPS of Salmonella enterica, serotype friedenau H909, was provided by H. Brade (Research Center Borstel, Borstel, Germany). It was prepared by the hot phenol-water procedure, purified by repeated ultracentrifugation, and converted into the sodium salt form by electrodialysis (22).
Chemicals
SB203580 and PD98059 were purchased from Calbiochem (Schwalbach, Germany). Abs against MAP kinases (p38, phospho-p38, p42/44 (ERK 1/2), phospho-p42/44 (ERK 1/2), JNK, and phospho-JNK) were purchased form New England Biolabs (Schwalbach, Germany). Anti-CD14 (MEM 18) was a gift from V. Horejsi (Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech Republic). Isotype control Abs used in culture experiments were obtained from BD PharMingen (Heidelberg, Germany).
Cell preparation and differentiation
PBMC were prepared from venous blood from healthy volunteer
donors using density gradient centrifugation (23).
Monocytes were isolated from PBMC by counterflow centrifugation as
previously described (24). The purity of the monocyte
fraction was determined using flow cytometric analysis of CD14
expression (consistently >95%) and positivity for
-naphthyl-esterase staining (>90%). For differentiation into
macrophages, monocytes were cultured for 7 days in Teflon bags
(Süd Laborbedarf, Gauting, Germany) containing RPMI 1640
supplemented with 2% (v/v) heat-inactivated human serum, 100 U/ml
penicillin G (Biochrom, Berlin, Germany), 100 µg/ml streptomycin
(Biochrom), 2 mmol/L L-glutamine (Biochrom), and 2 ng/ml
M-CSF (R&D Systems, Wiesbaden, Germany). After differentiation cells
were washed and cultured (4 x 105/well at
1 x 106/ml) in 24-well flat-bottom
microtiter plates (Nunc, Roskilde, Denmark) in RPMI 1640 medium
containing 10% (v/v heat-inactivated FCS (Biochrom) and 2 mmol/L
L-glutamine (Biochrom). Cell viability in the presence of
inhibitors was measured by trypan blue exclusion and by a
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and
was 95% of the viability of control (untreated) cultures.
Abs and flow cytometry
The following Abs were used for immunophenotyping of cells: anti-CD14 (RMO52; Coulter Diagnostics, Krefeld, Germany), anti-carboxypeptidase M (MAX1, provided by R. Andreesen, Department of Hematology and Oncology, University of Regensburg, Regensburg, Germany) (25), and anti-MMR (provided by S. Sozzani, Instituto di Ricerche Farmacologiche "Mario Negri," Milan, Italy) as well as the appropriate IgG1 and IgG2a isotype control Abs. Binding of the primary Abs was detected by the use of Cy5-labeled goat anti-mouse antiserum (Dianova, Hamburg, Germany). Briefly, 2 x 105 cells were stained at 4°C with saturating Ab concentrations as stipulated by the manufacturer. After staining the cells were washed, resuspended in PBS, and fixed with 3% paraformaldehyde until analysis in a FACSCalibur flow cytometer (BD Biosciences).
Determination of monokine release
For the detection of monokines culture supernatants were
harvested at the times indicated and frozen at -20°C until analysis.
The concentrations of TNF- in supernatants were determined using
quantitative ELISA provided by H. Gallati (Intex, Muttenz,
Switzerland). IL-10 ELISA was purchased from R&D Systems. The assays
were conducted as recommended by the manufacturer and as previously
described (26).
Analysis of MAP kinase phosphorylation
Cells (4 x 105) were lysed in 100 µl 2x sample buffer (125 mM Tris (pH 6.80, 4% SDS, 20% glycerol, 100 µM DTT, and 0.05% bromophenol blue), loaded onto a 12% SDS-PAGE gel, and run at 100 mA for 1.5 h. Cell proteins were transferred to nitrocellulose membrane (Sartorius, Gottingen, Germany) for 1.5 h at 75 V by wet blot at 4°C (Mini Protean 2, Bio-Rad, Munich, Germany). The nitrocellulose was then blocked with 5% nonfat dry milk (Glücksklee, Nestle, Frankfurt) in TBS with 0.1% Tween 20 for 2 h, washed and incubated with the primary Ab at 4°C overnight as recommended by the manufacturer. The blots were washed four times with TBS with 0.1% Tween 20 and incubated for 1 h with HRP-conjugated goat anti-rabbit IgG Ab (Dianova; p38, phospho-p38, ERK 1/2, phospho-ERK 1/2, JNK) or HRP-conjugated goat anti-mouse IgG Ab (Dianova; phospho-JNK). Immunoreactive bands were developed using a chemiluminescent substrate (ECL, Pharmacia-Amersham, Freiburg, Germany). Autoradiography was performed with exposure times of 15 s to 5 min, whichever were adequate for visualization.
Statistical analysis
Data obtained from independent experiments are presented as the mean ± SD and were compared by Student’s t test or for multiple comparisons by ANOVA. Differences were considered significant for p < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production in human
MDM
Human MDM were incubated with increasing concentrations of
M. avium strain SE01. Analysis after 12 h of culture
showed a dose-dependent increase in TNF- formation (Fig. 1
A), with 4–12 ng/ml TNF-
at a ratio of 10 mycobacteria/macrophage. Differing absolute amounts in
TNF- produced are due to donor variability, which can be quite
substantial. All experiments were performed at least five times using
cells from different donors, and the qualitative effects described here
were reproduced in all individuals. The highest peak of TNF-
production in response to M. avium was always detected 8–24
h after stimulation (Fig. 1B). For additional experiments a
mycobacteria-macrophage ratio of 3:1 or 10:1 was used, and supernatants
were harvested at 18 h.
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To analyze which receptor mediates the activation by M.
avium SE01, we measured TNF- formation in the presence or the
absence of inhibitory Abs against CD14 (27) or against the
MMR (28). Preincubation with the anti-CD14-Ab resulted
in a reduction of up to 80% of the M. avium-induced TNF-
formation (SE01; Fig. 2A),
whereas anti-MMR Ab did not show a significant effect (Fig. 2B). An IgG1 isotype control Ab used at the same
concentration did not affect TNF- secretion. Therefore, CD14, but
not the MMR, is involved in M. avium-induced TNF-
formation of human macrophages. Similar results were obtained when
M. avium-induced IL-10 formation was measured (data not
shown).
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Because MAP kinases are critical factors mediating cellular
responses to many external stimuli, we next examined MAP kinase
activation in response to M. avium infection. Macrophages
were stimulated with mycobacteria at a ratio of 3:1, and
phosphorylation of p38, JNK, and ERK1/2 was analyzed (Fig. 3). M. avium SE01 led to a
strong phosphorylation of p38 and JNK and ERK1/2 30–60 min after
stimulation. Control cells stimulated with LPS (10 ng/ml) showed a
signal of comparable intensity. The observed time courses of all three
MAP kinase families were similar.
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Because treatment with anti-CD14 mAbs blocked TNF-
formation, we next investigated whether it would also interfere with
MAP kinase phosphorylation, a critical prerequisite of MAP kinase
activation. Macrophages were incubated in the absence or presence of an
anti-CD14 Ab (5 µg/ml) or isotype control Ab for 45 min,
subsequently stimulated with mycobacteria for 30 min, and analyzed for
MAP kinase phosphorylation. Fig. 4
illustrates that preincubation with anti-CD14 almost completely
abrogated MAP kinase phosphorylation (ERK1/2 and p38) of MDMs in
response to M. avium SE01. Preincubation with the same
concentration of isotype control Ab had no effect. Thus, the
availability of CD14 is essential for MAP kinase activation by M.
avium.
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formation
ERK1/2 and p38 have both been shown to be pivotal in cytokine
formation induced by LPS (29). To further understand the
functional role of these kinases in the activation of macrophages
induced by M. avium, we used highly specific inhibitors of
either kinase and measured TNF- formation. Both inhibitors, SB203580
(p38) (18) and PD98059 (MAP kinase kinase, MEK)
(30), dose dependently reduced LPS-induced TNF-
formation of human macrophages by 85 and 80%, respectively (Fig. 5, A and C). In
contrast, TNF- formation of macrophages in response to M.
avium was completely unaffected by the p38 inhibitor SB203580
(Fig. 5B). However, the MEK inhibitor PD98059 did reduce
TNF- secretion of MDMs by up to 85% (Fig. 5D). The
latter result was confirmed by the use of a second and more potent MEK
inhibitor U0126 (data not shown).
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production in the presence of PD98059
was indeed a consequence of inhibited ERK phosphorylation, MDMs were
cultured in the presence or the absence of 10 µM of the MEK inhibitor
PD98059 for 45 min. Cells were stimulated for 30 min with M.
avium SE01, 10 ng/ml LPS, and 10 ng/ml PMA, and ERK
phosphorylation was analyzed. PD98059 inhibited M. avium
SE01-induced ERK phosphorylation (Fig. 6A). LPS-induced
phosphorylation of ERK was affected to a similar extent, as described
previously (31), whereas PMA-mediated activation, which is
known to stimulate cells via different and independent mechanisms, was
almost unaltered. The p38 phosphorylation in response to LPS and
M. avium SE01 was unaffected in the presence of PD98059
(Fig. 6B).
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formation is p38
independent
In contrast to its prominent effect on LPS-induced TNF-
formation, the p38 inhibitor SB203580 did not influence M.
avium SE01-induced TNF- secretion (Fig. 5
B). To
exclude that this effect was specific for a particular strain of
M. avium, we performed p38 inhibition experiments with
another clinical isolate of M. avium, the smooth opaque
variant of strain 2151. Human MDMs were preincubated with SB203580 and
subsequently stimulated with increasing concentrations of M.
avium 2151 SmO (Fig. 7B).
Corroborating the results obtained with M. avium SE01, no
inhibition was observed. Rather, there was a tendency to an increased
TNF- formation in the presence of SB203580, although this did not
attain statistical significance in all experiments (see Fig. 7B vs Fig. 5B). Because TNF- production was
always lower when using M. avium than when using LPS as a
stimulus, it appeared possible that the inhibitory effect of SB203580
was mostly quantitative, rather than qualitative. To test this
possibility, a wide range of LPS concentrations (0.01 pg/ml to 10
ng/ml) were used to induce both high and low amounts of TNF- in
MDMs. Indeed, TNF- formation was sensitive to inhibition by SB203580
at all given LPS concentrations (Fig. 7A). Therefore,
whereas p38 MAP kinase activity is essential for TNF- production
induced by LPS, it is not necessary for TNF- production induced by
M. avium.
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The activity of p38 is also important for the production of IL-10
by human monocytes (19). Therefore, we analyzed M.
avium-induced IL-10 production in the absence or presence of
SB203580. Fig. 8B shows that
the M. avium-induced IL-10 production of MDM was blocked by
70% when using SB203580, thus demonstrating that the inhibitor is
active in M. avium-infected macrophages. Similar to results
with LPS stimulation, the ERK inhibitor PD 98059 did not affect IL-10
production by MDM infected with M. avium (Fig. 8D), whereas LPS-induced IL-10 production was enhanced. In
conclusion, p38 MAP kinase activity is necessary, but ERK activity is
dispensable, for the IL-10 production of human macrophages stimulated
with M. avium.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-10 secretion. M. avium led to the
rapid phosphorylation of all three MAP kinase families in a
CD14-dependent manner. In contrast to LPS-induced signaling, activation
of ERK, but not p38 activity, was essential for the secretion of
TNF- in response to M. avium, whereas p38 activity, but
not ERK activity, was critical for IL-10 secretion induced by M.
avium. Therefore, macrophage-dependent orchestration of pro- vs
anti-inflammatory events is regulated very early during infection
with M. avium at the level of MAP kinase activity.
To date, most investigators have focused on the role of NF-
B in
mycobacteria-induced macrophage activation (32, 33). This
is the first study reporting that all three MAP kinase families (p38,
ERK1/2, and JNK) are rapidly phosphorylated in response to intact
viable M. avium. Our next goal was to understand in which
way M. avium-induced MAP kinase activation was causally
related to TNF- formation. p38 activity is of critical importance
for the release of TNF- and IL-1 in monocytes stimulated by LPS
(34). In brief, p38 activates MAP kinase-activated protein
kinase 2, which then phosphorylates heat shock protein 27, further
leading to the initiation of TNF- mRNA translation. The pyridinyl
imidazole SB203580, a cell-permeable, highly specific p38 inhibitor,
binds to the p38 ATP binding site (35), therefore
inhibiting the activity, but not the phosphorylation, of the enzyme.
Although SB203580 clearly reduced LPS-mediated TNF- formation,
M. avium-induced TNF- secretion, as shown for two
different clinical isolates, was not affected, even when 3 µM
inhibitor was used. This concentration is well above the
IC50 of 0.15 µM described by other
investigators (36). Even when the ratio of mycobacteria
per macrophage was raised to 10:1 and 30:1, no inhibitory effect of
SB203580 on M. avium-induced TNF- formation was seen.
This indicates that the p38-independent TNF- formation is not strain
or dose specific, but may represent a general reaction pattern of the
macrophage responding to M. avium and, possibly, other
mycobacteria. That there is a qualitative, rather than quantitative,
difference in cellular activation in response to mycobacteria
compared with LPS is further supported by our finding that the
LPS-induced TNF- was always sensitive to inhibition by the p38
inhibitor, even when very low concentrations of LPS, e.g., 50 pg/ml,
were used (Fig. 7A).
Only T cells were previously shown to release TNF- independently of
p38 activity (36). This is the first demonstration that in
macrophages also p38 activity may not be per se involved in TNF-
formation, but is instead closely linked to the stimulus used. Whereas
LPS from Gram-negative bacteria requires p38 activity for TNF-
production, mycobacteria such as M. avium do not. Our
findings suggesting a distinct role of p38 in mycobacterial infections
are corroborated by a very recent report by Chan et al.
(37), who show that SB203580 does not block, but rather
enhances, lipoarabinomannan-induced nitrite production in murine RAW264
macrophages. Other investigators demonstrated an inhibition of
LPS-induced nitrite formation by the same inhibitor
(38).
In contrast to TNF-, we found IL-10 production to be significantly
reduced in the presence of SB203580. IL-10 is an important regulator of
myeloid cells, which plays an overall anti-inflammatory role,
potently inhibiting the capacity of monocytes/macrophages to secrete
inflammatory cytokines as well as down-regulating their capacity to
serve as accessory cells (39). Previous studies
demonstrated that p38 activation is a key signaling step in the IL-10
biosynthesis induced by LPS (19). We now show that this
also holds true for the IL-10 production by macrophage induced by
mycobacteria. Because myeloid IL-10 production is regulated in an
autocrine/paracrine network by stimulatory cytokines such as TNF- or
IL-1 (40), one may argue that in our system the M.
avium-induced TNF- ultimately might lead to IL-10 formation by
inducing p38 activity. Although we have not formally ruled out this
possibility, we consider it unlikely, because blocking of M.
avium- induced TNF- formation by the MEK inhibitor PD98059 had
no influence on IL-10 formation.
The involvement of the ERK pathway was analyzed by the use of PD98059,
a selective inhibitor of MEK1, the dual specificity kinase that
activates ERK via phosphorylation on both threonine and serine residues
(41). We found that both the M. avium- and the
LPS-induced TNF- formation was drastically reduced in the presence
of PD98059, which effectively inhibited ERK1/2 phosphorylation to
either stimulus. Therefore, in contrast to p38, the ERK pathway is
critically important in the M. avium-induced activation and
subsequent TNF- formation of human MDMs.
Our data indicate that there might be an early branching point in the mycobacteria-induced activation cascade of the macrophage, at least with respect to cytokine induction, that fundamentally differs from that induced by LPS. Therefore, we analyzed whether this discrepancy would also be apparent at the level of receptor usage.
The MMR is a C-type lectin that mediates attachment to glycoconjugates
terminating in mannose, fucose, and N-acetylglucosamine. The
MMR has been shown to mediate phagocytosis of various mycobacterial
species (11, 42) and has been reported to trigger the
production of reactive oxygen intermediates by macrophages
(43), but other investigators failed to detect a role of
MMR in generation of O2-
or in the change in phosphorylation of protein tyrosine residues
(42). Our experiments using inhibitory Abs against the MMR
(28) did not reveal an important role for this receptor in
the M. avium-induced TNF- formation of human
MDMs.
A very prominent player in the macrophage activation cascade after
contact with bacterial compounds as well as mycobacterial components
such as liporarabinomannan is CD14, a cell surface,
glycosylphosphatidyl inositol-linked, 55-kDa glycoprotein expressed
predominantly on myelomonocytic cells (including monocytes and
macrophages) (12, 44, 45). We found MAP kinase activation
and cytokine formation induced by viable M. avium to be
dependent on CD14. The molecular mechanism by which CD14 mediates the
activation of MDM by intact mycobacteria is not clear. Due to the lack
of an intracellular signaling tail, CD14 on its own is not able to
transmit a signal into a cell. Recent discoveries show that CD14
interacts with Toll-like receptors (TLRs) to transmit a signal
(46). TLRs comprise a family of innate immune signaling
receptors that are capable of discriminating between bacterial
components originating from different sources (47). Recent
evidence suggests that TLR4 is essential for the recognition of
Gram-negative bacteria, whereas TLR2 is a key signaling factor in cell
responsiveness to isolated components of Gram-positive bacteria
(48) and of mycobacteria (49). With respect
to intact viable mycobacteria the situation might be even more complex.
Means et al. (50) reported that intact M.
tuberculosis may use both TLR2 and TLR4 to activate NF-B, and
Lien et al. (51) demonstrated that M.
avium-mediated TNF- formation by human PBMC could be only
partially inhibited by an anti-TLR2 Ab. This inhibition was
reflected at the level of NF-B signaling, as demonstrated in a panel
of TLR-transfected Chinese hamster ovary cells. It will be interesting
to investigate whether and to what extent TLR2-mediated signaling
contributes to MAP kinase activation and cytokine formation by primary
macrophages in response to intact M. avium organisms.
Regardless of whether CD14 or TLR2 is the first step in the activation process, CD14 is critically involved in both M. avium-induced ERK and p38 activation. Our data suggest that the branching point in M. avium-induced signal transduction is downstream of CD14 but upstream of the MAP kinase level. Most signals transmitted via TLRs make use of an adapter molecule, MyD88, although MyD88-independent pathways are also being identified (52). Whether differential MAP kinase usage is directly related to differential TLR and/or MyD88 usage remains to be determined.
In summary, the requirement for activated MAP kinases clearly differs
between M. avium and LPS-triggered cytokine secretion.
Whereas p38, and not ERK, activity is necessary for IL-10
secretion, ERK activity, and not p38, is indispensable for the
generation of TNF-. This distinct usage of MAP kinase pathways
in the production of regulatory cytokines offers an intriguing novel
target for therapeutic intervention in mycobacteria-induced
inflammation.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Norbert Reiling, Division of Molecular Infection Biology, Department of Immunochemistry and Biochemical Microbiology, Research Center Borstel, D-23845 Borstel, Germany. E-mail address: nreiling{at}fz-borstel.de
3 Abbreviations used in this paper: MMR, macrophage mannose receptor; MAP, mitogen-activated protein kinase; JNK, c-Jun NH2-terminal kinase; MEK, MAP kinase kinase; ERK, extracellular signal-regulated kinase; MDM, monocyte-derived macrophage; TLR, Toll-like receptor.
Received for publication July 17, 2000. Accepted for publication July 9, 2001.
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References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
, tumor necrosis factor and interleukin-6 in Mycobacterium tuberculosis and M. avium infections. Immunobiology 191:520.[Medline]
in human monocytes by lipoarabinomannan of Mycobacterium tuberculosis. Infect. Immun. 64:399.[Abstract]
and interferon-. Immunology 92:413.[Medline]
and tumor necrosis factor- by Mycobacterium tuberculosis components. J. Clin. Invest. 91:2076.
: role of the p38 and p42/44 mitogen-activated protein kinases. J. Immunol. 160:920. receptor I (CD64)-negative monocytes, a minor human monocyte subpopulation with high accessory and antiviral activity. Eur. J. Immunol. 23:3126.[Medline]
production by human monocytes involves the raf-1/MEK1-MEK2/ERK1-ERK2 pathway. Infect. Immun. 67:3824.B in different cell types through reactive oxygen intermediates. J. Immunol. 161:4834.B via induction of inflammatory cytokines. Cell. Immunol. 191:117.[Medline]
production in a manner distinct from LPS activation of monocytes. J. Immunol. 162:659.B signaling pathways. Infect. Immun. 69:2001. and interleukin-10 expression. Eur. J. Immunol. 26:1580.[Medline]
B activation requires a Rac1-dependent pathway. Nat. Immunol. 1:533.[Medline]This article has been cited by other articles:
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 M. Yadav, L. Clark, and J. S. Schorey Macrophage's Proinflammatory Response to a Mycobacterial Infection Is Dependent on Sphingosine Kinase-Mediated Activation of Phosphatidylinositol Phospholipase C, Protein Kinase C, ERK1/2, and Phosphatidylinositol 3-Kinase J. Immunol., May 1, 2006; 176(9): 5494 - 5503. [Abstract] [Full Text] [PDF]
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B. K. W. Cheung, D. C. W. Lee, J. C. B. Li, Y.-L. Lau, and A. S. Y. Lau A Role for Double-Stranded RNA-Activated Protein Kinase PKR in Mycobacterium-Induced Cytokine Expression J. Immunol., December 1, 2005; 175(11): 7218 - 7225. [Abstract] [Full Text] [PDF]
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 A. Blumenthal, J. Lauber, R. Hoffmann, M. Ernst, C. Keller, J. Buer, S. Ehlers, and N. Reiling Common and Unique Gene Expression Signatures of Human Macrophages in Response to Four Strains of Mycobacterium avium That Differ in Their Growth and Persistence Characteristics Infect. Immun., June 1, 2005; 73(6): 3330 - 3341. [Abstract] [Full Text] [PDF]
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M. K. Dahle, G. Overland, A. E. Myhre, J. F. Stuestol, T. Hartung, C. D. Krohn, O. Mathiesen, J. E. Wang, and A. O. Aasen The Phosphatidylinositol 3-Kinase/Protein Kinase B Signaling Pathway Is Activated by Lipoteichoic Acid and Plays a Role in Kupffer Cell Production of Interleukin-6 (IL-6) and IL-10 Infect. Immun., October 1, 2004; 72(10): 5704 - 5711. [Abstract] [Full Text] [PDF]
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M. Yadav, S. K. Roach, and J. S. Schorey Increased Mitogen-Activated Protein Kinase Activity and TNF-{alpha} Production Associated with Mycobacterium smegmatis- but Not Mycobacterium avium-Infected Macrophages Requires Prolonged Stimulation of the Calmodulin/Calmodulin Kinase and Cyclic AMP/Protein Kinase A Pathways J. Immunol., May 1, 2004; 172(9): 5588 - 5597. [Abstract] [Full Text] [PDF]
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) and 3 µM
SB203580 (
) for 45 min and were subsequently incubated with
increasing concentrations of LPS (A) and M.
avium strain 2151 SmO (B). Supernatants were
harvested after 18 h, and TNF-