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Mitogen-Activated Protein Kinase/Nuclear Factor-
B Pathway1
Max Planck Institute of Psychiatry, Department of Endocrinology (P.L., J.G., Z.K., U.H., M.P.P., G.K.S., U.R.), D-80804 Munich, Germany; and Laboratorio Fisiologia y Biologia Molecular (A.C.N., E.A.), FCEN, Universidad de Buenos Aires and CONICET, 1427 Buenos Aires, Argentina
Address all correspondence and requests for reprints to: Ulrich Renner, Ph.D., Max Planck Institute of Psychiatry, Department of Endocrinology, Kraepelin Street 10, D-80804 Munich, Germany. E-mail: renner{at}mpipsykl.mpg.de
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Abstract |
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mitogen-activated protein kinase and
the inhibitor (I
B) of nuclear factor- B. Nuclear factor- B was
activated by LPS in TtT/GF cells. Functional studies demonstrated that
My4 (an antibody blocking the interaction between LPS/LBP and CD14),
SB203580, (a specific inhibitor of p38 mitogen-activated protein
kinase phosphorylation), dexamethasone, and the messenger RNA
translation inhibitor cycloheximide all inhibited LPS-induced IL-6
production by TtT/GF cells and mouse pituitary FS cells. LPS-induced
intrapituitary IL-6 may modulate the function of anterior pituitary
cells during bacterial infection/inflammation. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Lipopolysaccharide (LPS), a component of the outer layer of the cell
wall of gram-negative bacteria (4), is a potent activator
of the immune system (5). It induces the subsequent
release of tumor necrosis factor (TNF)-, interleukin (IL)-1, and
IL-6 from macrophages and monocytes (6). Although LPS
alone can activate these cells, its stimulatory potency is strongly
enhanced when it is coupled to LPS-binding protein (LBP)
(7), which is present in serum (8). In
monocytes and macrophages, it is known that membrane-bound CD14 (mCD14)
binds free LPS or LPS/LBP complex (9). mCD14-negative cell
types, like endothelial cells or smooth muscle cells, need soluble
CD14, which is present in serum, for an optimal response to LPS
(10). The LPS/LBP/CD14 complex subsequently interacts with
the Toll-like receptor-4 (Tlr4), a member of the Toll protein family
(11, 12). In immune cells, LPS induces the activation of
nuclear factor-B (NF-B) (13), but the preceding
signaling cascade is largely unknown; so far, only the participation of
mitogen-activated protein kinase (MAPk) kinase-3 and p38 MAPk
(14), or the p42/44 MAPk (15), has been
shown.
Cytokines not only represent a lymphocyte message but are produced by
pituitary cells themselves (16, 17, 18). With respect to IL-6,
folliculostellate (FS) cells have been identified as the source of this
cytokine within the normal pituitary (19, 20). IL-6
production by FS cells is inhibited by glucocorticoids
(21) and stimulated by neuroendocrine factors, such as
pituitary adenylate cyclase-activating polypeptide (PACAP) and
vasoactive intestinal peptide (22, 23, 24). LPS and cytokines,
like TNF- and IL-1, also enhance IL-6 production
(25, 26, 27). There is evidence that the hormone stimulatory
potency of the above-mentioned substances is mediated, in part, through
the subsequent paracrine action of IL-6, which is a potent stimulator
of ACTH, GH, PRL, FSH, and LH secretion (16, 17).
We have studied whether essential components needed for the direct action of LPS, such as CD14 and Tlr4, are expressed in the FS TtT/GF mouse pituitary cell line and in mouse pituitaries, and we have characterized the LPS signaling pathway in FS cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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MAPk
phosphorylation inhibitor SB203580 (14) was obtained from
Calbiochem (Bad Soden, Germany).
Cell culture
TtT/GF cells were grown in 48-multiwell plates at 37 C and 5%
CO2 in DMEM (pH 7.3) supplemented with 2% FCS,
2.2 g/liter NaHCO3, 10 mM HEPES, 2
mM glutamine, 2.5 mg/liter amphotericin
B, 105 U/liter
penicillin-streptomycin, 5 mg/liter insulin, 5 mg/liter transferrin, 20
mg/liter sodium selenite, and 30 pM
T3. TtT/GF cells were cultured at 37 C and 5%
CO2 until they were confluent. After a monolayer
had formed (approximately 70,000 cells per well in 48-well plates) as
previously reported, the cells did not grow further (29).
The monolayer was washed with PBS, and serum-free culture medium was
added for 48 h to wash out any remaining serum. The cells were
then washed again with PBS and stimulated as described below.
For primary cell culture, pituitaries from 12-week-old male C57BL/6 mice were enzymatically and mechanically dispersed as previously described for rat pituitaries (30). Dispersed cells were seeded at an initial density of 100,000 cells per well in 48-well plates and cultivated in D-Val-MEM (to suppress fibroblast growth) (30) supplemented with 10% FCS and additives indicated above for TtT/GF cell culture. After an initial attachment period of 48 h, followed by a serum washout period of 48 h, the cells were used for stimulation experiments as indicated.
Stimulation and measurement of IL-6
All stimulation or inhibition experiments were performed in the
appropriate culture medium in the presence or absence of FCS (2%), as
indicated. Before and after the treatment period, cell viability and
numbers were routinely monitored to ensure that these parameters did
not change during the experiment. Cell viability was determined
microscopically after ethidium bromide/acridine orange staining. Cell
numbers were determined with an adapted Coulter counter, as previously
described (29).
Mouse IL-6 was measured according to the manufacturer’s instructions, by enzyme-linked immunosorbent assay (R&D Systems, Minneapolis, MN), as previously reported (29). The detection limit of the assay was 3 pg/ml. The intraassay and interassay coefficients of variation were 3.4% and 6.4%, respectively.
Determination of cAMP and inositol phosphate
Studies on second messengers were performed with confluent
TtT/GF cell cultures that had been cultivated for 48 h in
serum-free culture medium before the experiments.
To measure inositol 1-phosphate (Ip1), Ip2, and Ip3, monolayers of TtT/GF cells were incubated in 12-well plates for 20 h in serum-free culture medium containing 2.5 µCi/well myo-3H-inositol (Amersham Pharmacia Biotech, Braunschweig, Germany). The medium containing myo-3H-inositol was removed, and the monolayers were washed 3 times with PBS. The cells were treated with 10 mM LiCl for 15 min and stimulated with LPS for an additional 60 min in the presence (2%) or absence of FCS. The reaction was terminated by the addition of 1 ml ice-cold methanol (96%). Subsequently Ip1, Ip2, and Ip3 values were determined as previously described (31).
cAMP was determined as described by Matsumoto et al. (24). TtT/GF monolayer cell cultures were incubated for 24 h, with or without LPS, in the presence (2% FCS) and absence of serum. In the cell culture supernatants, cAMP was measured by RIA (NEN Life Science Products, Cologne, Germany).
RT-PCR for mouse mCD14 and Tlr4
For RT-PCR, total cellular RNA was isolated from TtT/GF cells,
mouse anterior pituitary, and mouse spleen by guanidinium
isothiocyanate, followed by the phenolchloroform method
(32). RT of 1 µg RNA was performed with Superscript-II
(Life Technologies, Inc./BRL, Karlsruhe, Germany) for
1 h at 45 C, followed by a denaturation step at 94 C for 1 min.
With the complementary DNA (cDNA) template obtained, 35-cycle PCR was
performed with specific primers (Table 1
). Each cycle consisted of denaturation
at 94 C for 1 min, annealing of primers at 60 C for 1 min, and chain
extension at 72 C for 1 min. Amplified products were electrophoresed in
1.8% agarose gel and stained with ethidium bromide.
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) were constructed according to the published DNA sequences
(GenBank accession numbers NM009841 for mouse CD14 and AF185285 for
mouse Tlr4).
Determination of phosphorylation of p38 MAP kinase and
IB
Confluent 75-cm2 culture flasks of TtT/GF
cells were given a change of medium (with and without FCS) and then,
2 h later, stimulated with LPS for 15, 30, and 60 min. The cells
were washed with ice-cold PBS, lysed with SDS sample buffer [62.5
mM Tris-HCl (pH 6.8), 2% wt/vol SDS, 10% glycerol, 50
mM dithiothreitol, 0.1% wt/vol bromophenol blue], and
collected in Eppendorf (Hamburg, Germany) tubes.
After the samples were sonicated and heat-treated for 3–5 min at 95 C,
20 µl from each sample were fractionated on a 10% SDS-polyacrylamide
gel and then electrotransferred onto a nitrocellulose membrane
(Amersham Pharmacia Biotech, Buckinghamshire, UK). The
immunoreactive products on the membranes were detected using
PhosphoPlus IB- (Ser32), and p38 MAPk (Thr 180/Tyr 182)
antibody kits (New England Biolabs, Inc., Schwalbach,
Germany). In brief, the membranes were treated with 5% wt/vol nonfat
milk protein in TBST [50 mM Tris (pH 7.5), 150
mM NaCl, 0.1% Tween-20] for 1 h at room temperature,
and then overnight at 4 C in the primary antibodies diluted 1:1000 in
2.5% nonfat milk protein in TBST. After a 20-min wash in TBST, the
membranes were incubated at room temperature for 1 h in a 1:2000
dilution of the hydrogen peroxidase-conjugated secondary antibody in
2.5% nonfat milk protein in TBST. The membranes were washed in TBST
and then incubated with LumiGLO for 1 min at room temperature and then
immediately exposed to Lumi-Film chemiluminescent detection film
(Roche Diagnostics GmbH, Mannheim, Germany).
Determination of transcriptional activity of NF-B
TtT/GF cells (200,000 cells/well) were transfected with
lipofectamine in Optimem medium (Life Technologies, Inc./BRL) using 0.7 mg of the B/luciferase (B-LUC)
reporter plasmid and 0.3 mg of pRL-Tk, used as second reporter control
plasmid (Promega Corp., Mannheim, Germany). After 6.5
h, the medium was changed to DMEM with FCS 2%. After an overnight
incubation, the cells were given fresh DMEM containing 2% FCS and were
stimulated with LPS. After 6 h, the cells were washed with PBS,
and the LUC activity was measured with a dual reporter kit
(Promega Corp.). Reporter plasmid for B sites was
provided by Dr. M. Bell (Mayo Clinic, Rochester, MN) and has been
described elsewhere (33).
Statistics
Each of the experiments was repeated at least three times. The
individual experiments were performed with quadruplicate wells. ANOVA,
in combination with Scheffe’s test, was used for statistics. The data
are expressed as mean ± SE.
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Results |
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), which is needed for the LPS/LBP
complex to bind to the cell membrane.
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).
LPS stimulation of IL-6 production by TtT/GF cells
TtT/GF cells secreted low amounts of IL-6 in serum-free cell
cultures during 32-h time course studies (Fig. 2A). The addition of 2% FCS to the cells
induced no further increase in IL-6 production. In the absence of
serum, 100 ng/ml LPS significantly stimulated IL-6 production only
after 24 h. However, in the presence of 2% FCS, a tremendous
stimulation of the IL-6 production was observed in response to LPS
(Fig. 2A). IL-6 secretion was significantly elevated after 2 h and
linearly increased during a 32-h stimulation period. In dose-response
studies, 1 ng/ml LPS, in the presence of serum, significantly
stimulated IL-6 production. Maximal stimulation was obtained at a
concentration of 100 ng/ml LPS (Fig. 2B). In the absence of FCS, LPS
induced a significant increase in IL-6 production only at a
concentration of 100 ng/ml LPS, and maximal stimulation was achieved at
1000 ng/ml. Higher concentrations of LPS did not further stimulate IL-6
secretion (data not shown). Studies on the serum-dependency of
LPS-induced IL-6 secretion demonstrated that 0.5% FCS was sufficient
to induce a significant stimulatory effect of LPS. Saturation of the
IL-6-stimulating effect of LPS was achieved at 2% FCS, and no further
increase of the stimulatory potency of LPS was observed at higher
concentrations of FCS (Fig. 2C). It should be noted that, because FCS
is not a clearly defined substrate, variations of the LPS-induced IL-6
secretion were observed with different batches of FCS.
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). The inhibitory effect of
dexamethasone on LPS-induced IL-6 stimulation could be reversed by the
glucocorticoid receptor antagonist RU486. This clearly indicates that
functional glucocorticoid receptors participate in the regulation of
IL-6 secretion in TtT/GF cells.
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To test whether CD14 is involved in the LPS-induced IL-6 production by
TtT/GF cells, the effect of My4, an antibody which blocks the
interaction between LPS/LBP complex and CD14 (28), was
investigated. Although the antibody preparation itself slightly
stimulated IL-6 secretion by TtT/GF cells, My4 dose-dependently
inhibited the IL-6 stimulatory effect of LPS (Fig. 4). PACAP-induced IL-6 secretion was not
affected by My4, indicating that the antibody specifically blocks
LPS-stimulated IL-6 production.
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). Similar results were
obtained for Ip-2 and Ip-3 (data not shown). LPS did not alter cAMP
production, both in the presence and absence of FCS. In contrast, PACAP
stimulated cAMP production, whereas inositolphosphate turnover was not
affected (Table 2).
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MAPk or p42/44 MAPk is involved in LPS signaling. We found that
p38 MAPk was phosphorylated in TtT/GF cells in response to LPS.
Under serum-free conditions, LPS slightly induced p38 MAPk
phosphorylation; but, in the presence of serum, a strong stimulation
was observed (Fig. 5A). Time course
studies demonstrated the appearance of phosphorylated p38 MAPk
within 15 min, and maximal stimulation was achieved at 30 min (Fig. 5B). To demonstrate the involvement of phosphorylated p38 MAPk in
LPS-induced IL-6 secretion, SB203580, a specific inhibitor of p38
MAPk phosphorylation (14), was tested for its suppressive
effect on LPS-stimulated IL-6 production. Treatment of TtT/GF cells or
mouse pituitary cell cultures with SB203580 completely abolished the
LPS-induced IL-6 production (Fig. 6).
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B is activated
downstream of p38 MAPk. Stimulation of TtT/GF cells with 100 ng/ml
LPS serum-dependently induced phosphorylation of IB (inhibitor of
NF-B) within 15 min; maximal phosphorylation was achieved after 60
min of incubation (Fig. 7A).
Phosphorylation of IB was only slightly induced under serum-free
conditions (data not shown). After IB phosphorylation, the
IB/NF-B complex (in which NF-B is transcriptionally inactive)
dissociates, and NF-B becomes transcriptionally active
(34). To demonstrate the latter, TtT/GF cells were
transiently transfected with a B-LUC reporter plasmid responsive to
transcriptionally active NF-B. High basal levels of LUC activity
indicate that the cells were efficiently transfected with the B-LUC
construct and that the constitutive basal B activity is high.
Nevertheless, the LUC activity of the reporter plasmid was
significantly induced by LPS in TtT/GF cells (Fig. 7B).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Although free LPS is effective in immune and other cell types, its activity is strongly enhanced when it forms a complex with LBP, which is present in serum (7). We found that LPS-induced IL-6 production by TtT/GF cells was dramatically enhanced in the presence of FCS. The poor IL-6 response to LPS stimulation, reported in previous studies, could therefore be attributable to the serum-free conditions used in these experiments. The cellular binding site for LPS is CD14, which binds free LPS with low affinity and LPS/LBP with high affinity (9). We demonstrated that mCD14 is expressed in TtT/GF cells. However, mCD14 is only anchored in the outer layer of the phospholipid membrane and has no transmembrane domain or intracellular signaling domain (38). Therefore, mCD14 is considered to be necessary only for optimal presenting of the LPS/LBP complex to the LPS signal transducer, which has recently been identified as Tlr4 (12). The latter belongs to the family of Toll proteins, which have been shown to play a central role in immune defense systems in plants, insects, and vertebrates (11). Like most of the Toll proteins, Tlr4 is a type I transmembrane protein with a leucine-rich repeat extracellular domain, and a cytoplasmatic domain homologous to the one of the IL-1 receptor (11). Studies in immune cells have shown that Tlr4 is specific for LPS of gram-negative bacteria, whereas a similar protein, Tlr2, mediates immune effects induced by LPS-negative gram-positive bacteria (39). We demonstrated that Tlr4 is expressed in TtT/GF cells. Thus, both CD14 and Tlr4 (which are essential tools for the action of LPS) are present in TtT/GF cells.
At present, neither the mechanism by which the LPS/LBP/CD14 complex interacts with Tlr4 nor the initial steps of LPS signaling are known in immune cells. We found that, in TtT/GF cells, LPS stimulated the phosphoinositol turnover but did not affect cAMP production. Our findings could be explained by the similarity of the cytoplasmatic domain of Tlr4 with the intracellular domain of the IL-1 receptor. It has been shown that the IL-1-induced IL-6 secretion within the pituitary involves the phospholipid/protein kinase C pathway (40).
In contrast to the initial processes, the final steps of LPS signaling
are known. In different types of immune cells, either p38 MAPk
(14) or p42/44 MAPk (15) is involved in LPS
signal transduction pathways. We demonstrated that, in TtT/GF cells,
phosphorylation of p38 MAPk is rapidly induced by LPS. Activated
p38 MAPk then phosphorylates IB of the IB/NF-B complex,
which induces complex dissociation (34) and the release of
the active transcription factor NF-B. Activation of NF-B
represents the endpoint of LPS signaling in LPS-responsive cell types,
and the inducible expression of the IL-6 gene is known to depend on
NF-B (41).
Functional studies confirmed the involvement of some of the above
mentioned components or signaling events in LPS-induced IL-6 production
in TtT/GF cells. My4, an antibody which blocks the interaction of
LPS/LBP complex with CD14 (28), inhibited LPS-induced IL-6
secretion. SB203580, a specific inhibitor of p38 MAP kinase
phosphorylation (14), almost completely suppressed IL-6
production in response to LPS. In addition, we have shown that IL-6
stimulation by LPS was blocked by dexamethasone. It needs to be
clarified how glucocorticoids inhibit LPS-induced IL-6 production in
TtT/GF cells; but, most likely, activated glucocorticoid receptors
represent suppressive counterparts of NF-B and might act as
repressors at the level of IL-6 transcription (42).
Cycloheximide, which suppresses mRNA translation, almost completely
inhibited LPS-induced production of IL-6, suggesting that LPS does not
stimulate the rapid release of IL-6 from already existing intracellular
stores but induces de novo synthesis of the cytokine.
CD14 and Tlr4 expression was also demonstrated in normal mouse pituitary. In primary mouse pituitary cell cultures, LPS serum dependently stimulated IL-6 secretion; the latter was suppressed by My4, SB203580, glucocorticoids, and cycloheximide. The identical findings obtained in TtT/GF and mouse pituitary cell cultures indicate that normal mouse pituitary FS cells, which are the source of IL-6 in mouse pituitary, are the intrapituitary target of LPS, although the cellular localization of CD14 and Tlr4 in normal FS cells needs to be confirmed. In view of the ongoing discussion regarding the origin and function of FS cells (43), our data concerning the expression of mCD14 and Tlr4 suggest that these cells probably represent pituitary tissue-specific, macrophage-like cells. However, in previous studies, it has been shown that macrophage markers are not expressed in the majority of FS cells but only in a subpopulation of FS cells that are considered to be derived from the lymphoid dendritic cell lineage (44, 45, 46). It could be possible that only this latter subset of FS cells participates in the intrapituitary response to LPS and that the TtT/GF cell line was established from this particular subpopulation of FS cells. However, much more work is necessary to clarify whether different FS cell subpopulations with distinct intrapituitary functions exist.
An important stimulator of IL-6 production by FS cells is PACAP (22, 23, 24). During infection/inflammation, FS cells are affected in vivo, both by LPS and by physiological concentrations of PACAP, which is released into the hypophysial portal blood vessels perfusing the anterior pituitary. Under these conditions, LPS and PACAP might interact to influence IL-6 production. However, in FS cells, the signal transduction pathway and the molecular mechanisms of PACAP-induced IL-6 secretion remain unknown. Future studies on LPS/PACAP interactions would be important to clarify the mechanisms by which IL-6 production is affected in FS cells in (patho-)physiological conditions.
In summary, we have demonstrated the mechanism by which LPS stimulates the production of IL-6 by pituitary FS cells. By its well known stimulatory action on hormone secretion, LPS-induced intrapituitary IL-6 might contribute, in a paracrine manner, to the interactive processes between the endocrine and immune system during acute or chronic inflammation or infection.
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Acknowledgments |
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Footnotes |
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Received April 24, 2000.
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References |
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mitogen-activated protein kinase in lipopolysaccharide-stimulated
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