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First Department of Internal Medicine, Nagoya University School of Medicine, Nagoya 466, Japan
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Abstract |
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had similar effects, but much less potency. IL-6 showed a
profound stimulatory, but only a long term (>20 h), effect. IL-2 did
not influence POMC expression. In contrast, interferon- (IFN) and
IFN-
showed acute stimulatory effects (
4 h) followed by marked
inhibitory effects (>8 h). Although the acute effects of IL-1ß,
IL-6, and tumor necrosis factor- alone were minimal, they
significantly potentiated the stimulatory effect of CRH on POMC
expression. Finally, pretreatment of the cells with a broad spectrum
tyrosine kinase inhibitor, genistein, abolished or significantly
diminished the effects of all cytokines except IFNs. Our results
suggest that 1) each cytokine tested has a distinct effect on POMC gene
expression; 2) there are positive cross-talk effects between CRH and
cytokines at the corticotroph level; and 3) tyrosine phosphorylation
cascades are involved in the intracellular signaling mechanisms of some
cytokines. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In addition to the classical neuroendocrine responses to stress, the HPA axis has been shown to respond to immunological challenges. Recent studies demonstrate that various cytokines generated during infectious stress are involved in the regulation of the HPA axis, establishing the concept of immune-neuroendocrine interaction (2, 3). In many cases, cytokines have been shown to influence ACTH secretion by acting through the hypothalamus and modulating CRH secretion. Some cytokines, however, may also have direct effects on corticotroph cells in the anterior pituitary. In any event, the effects of cytokines on ACTH secretion have been well characterized through both in vivo and in vitro studies.
On the other hand, the effects of cytokines on ACTH synthesis,
especially on the expression of the POMC gene that encodes ACTH and
related neuropeptides, are not nearly as well characterized.
Furthermore, intracellular signaling pathways of the cytokines that
mediate the regulation of POMC gene transcription largely remain to be
clarified. Thus, in this paper, we studied the effects of
representative cytokines such as IL-1ß, IL-2, IL-6, tumor necrosis
factor- (TNF), interferon- (IFN), and IFN, either alone
or combined with CRH, on POMC gene expression using the AtT20 mouse
corticotroph tumor cell line transfected stably with the POMC
5'-promoter-luciferase fusion gene. We also tried to elucidate the
possible role of tyrosine phosphorylation cascades in the intracellular
signaling of each cytokine using a specific inhibitor of tyrosine
kinases, because the mechanisms are shown to be involved throughout
most of the signal transduction of cytokines in nonendocrine cells
(4).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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were
obtained from Boehringer Mannheim (Indianapolis, IN), and
recombinant mouse IFN and IFN were obtained from Hycult
Biotechnology (Uden, The Netherlands) and Genzyme (Cambridge, MA),
respectively. CRH was obtained from the Peptide Institute (Osaka,
Japan), and forskolin, 8-bromo-cAMP (8Br-cAMP), and
4',5,7-trihydroxyisoflavone (genistein) were purchased from Sigma (St.
Louis, MO).
Transfection and cell culture
Establishment of the AtT20PL cell line used in this study was
described previously (5). Briefly, AtT20/D16v mouse corticotroph cells
were transfected stably with the plasmid (pA3Luc) (6) containing an
approximately 0.7-kilobase XmnI fragment of the rat POMC
gene 5'-promoter (-708 to +64; +1 indicates the transcription start
site), and a representative clone, designated AtT20PL, was used for the
subsequent experiments. Several other clones obtained at the same time
were used when necessary.
The cells were maintained in a T-75 culture flask with DMEM (Life Technologies, Grand Islands, NY) supplemented with 10% FBS (Life Technologies) and antibiotics (50 µU/ml penicillin and 50 µg/ml streptomycin; Life Technologies) under a 5% CO2-95% air atmosphere at 37 C. Culture media were changed twice a week, and the cells were subcultured once a week.
Experiments
For each experiment, AtT20PL cells were plated in 3.5-cm
diameter culture dishes with approximately 50% confluence. The next
day, the culture media were changed to DMEM supplemented with 1% FBS,
and the cells were further cultured for 4 days, during time which the
culture media were changed every other day.
On the day of each experiment, solutions for all test reagents, in 1000-fold concentration, or solvent alone were added directly to the culture medium of each dish, and the cells were incubated for the designated period. At the end of incubation, the culture media were removed, and the cells were harvested for luciferase assay (see below). In the experiments in which ACTH secretion was studied, the culture medium was changed to the serum-free medium before the addition of test reagents. After the cells were incubated for 24 h, the culture medium from each dish was collected for ACTH assay (see below).
We carried out preliminary experiments using different clones of the stable transformants other than AtT20PL and confirmed that the results obtained show common characteristics among the clones, although some qualitative differences in the time course and the magnitude of the effects were observed.
Luciferase assay
The luciferase assay was performed as previously described (7)
with some modifications. At the end of each experiment, the cells were
washed twice with PBS without Ca2+ and Mg2+;
harvested with lysis buffer containing 1% (vol/vol) Triton X-100, 25
mM glycylglycine (pH 7.8), 15 mM
MgSO4, 4 mM EGTA, and 1 mM
dithiothreitol (DTT); and centrifuged at 18,000 x g
for 30 min. For luciferase assay, 100 µl of each supernatant were
added to 400 µl assay buffer containing 25 mM
glycylglycine (pH 7.8), 15 mM MgSO4, 4
mM EGTA, 15 mM potassium phosphate buffer (pH
7.8), 2 mM ATP, 1 mM DTT, and 0.5
mM coenzyme A. The reactions were started by the injection
of 200 µl luciferin solution containing 0.2 mM
D-luciferin (Wako Chemical Co., Osaka, Japan), 25
mM glycylglycine (pH 7.8), 15 mM
MgSO4, 4 mM EGTA, and 2 mM DTT.
Light output was measured for 20 sec at room temperature using a
luminometer (Berthold Lumat LB9501, Bad Wildbad, Germany).
ACTH assay
ACTH in culture medium was measured by radioimmunometric assay
(ACTH immunoradiometric assay kit, Mitsubishi Chemical, Tokyo,
Japan).
Protein and cell viability assays
To determine the effect of each cytokine on cell growth and/or
viability, a separate experiment for each test substance was carried
out. AtT20PL cells were treated with a cytokine or vehicle for the
designated time interval during which the maximal effect was obtained
(28, 32, 24, and 32 h for IL-1ß, IL-6, TNF, and IFNs,
respectively). At the end of incubation, cells were lysed by the
freeze-thaw method using PBS without Triton X-100 and DTT to avoid
interference with the protein assay and were centrifuged at 18,000
x g for 30 min. The protein concentration in the
supernatant was determined using a micro-BCA protein assay kit (Pierce
Chemical Co., Rockford, IL).
As shown in Results, some cytokines (IFNs) markedly reduced
the POMC promoter activity. To determine whether the effect is due to
cytotoxicity of the cytokine, AtT20PL cells were treated with IFN
for 32 h, and cell viability was estimated by a trypan blue dye
exclusion procedure.
Data analyses
Most of the experiments were carried out more than twice, and a
representative set of data is presented. Samples in each group of the
experiments were in triplicate or quadruplicate. All data were
expressed as the mean ± SEM. When the statistical
analyses were performed, data were compared by one-way ANOVA with
Fisher’s multiple range test, and P < 0.05 was
considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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2.3-fold increase) was observed 28 h
after the start of incubation (Fig. 1A
).
The dose-response study at 28 h showed that the significant
stimulatory effect was obtained at a concentration as low as 1
pM, with the maximal effect at 100 pM.
Furthermore, the short term time-course (0–5 h) and dose-response
studies revealed that there was another small peak (1.2-fold
increase) 2–3 h after the start of incubation (Fig. 1B), thus
representing a biphasic pattern of the effect. IL-1ß did not
influence the growth rate and/or the viability of the cells during the
incubation (data not shown). This was also the case with IL-6 and
TNF (data not shown).
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Effect of IL-6 on POMC 5'-promoter activity
IL-6 stimulated POMC gene expression in a time-related manner. The
long term (0–32 h; Fig. 2) and short
term (data not shown) time course studies showed that the increase was
observed at 3 h and was maximal (1.7-fold increase) at 32
h after the start of incubation, thus representing the monophasic
pattern of the effect. The dose-response study at 32 h showed that
the significant stimulatory effect was obtained only at 1
nM.
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on POMC 5'-promoter activity stimulated POMC gene expression in a time- and dose-related
manner. The long term time-course study (0–32 h) showed that the
maximal effect (1.3-fold increase) was observed 20 h after the
start of incubation (Fig. 3A). The
dose-response study at 24 h showed that the significant
stimulatory effect was obtained at a concentration as low as 10
pM, with the maximal effect at 100 pM.
Furthermore, the short term time-course (0–5 h) and dose-response
studies revealed that, like IL-1ß, there was another small peak
(1.1-fold increase) 3–4 h after the start of incubation (Fig. 3B).
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and IFN on POMC 5'-promoter activity and IFN showed quite different effects from other
cytokines on POMC gene expression; the long term time-course (0–32 h)
and dose-response studies showed that IFN exerted an acute (4 h),
mild stimulatory effect followed by a delayed, potent inhibitory effect
(8 h or later; Fig. 4A). A similar effect
was obtained with IFN (Fig. 4B). To determine the cytotoxicity of
the IFNs, we carried out the trypan blue dye exclusion procedure after
32-h treatment with IFN. The results showed that the cytokine did
not affect the cell viability [the percentages of surviving cells were
90.7% (254 of 280) and 90.0% (253 of 281) in the control and
IFN-treated groups, respectively]. On the other hand, protein assay
showed that IFN, but not IFN, had a mild inhibitory effect on
cell growth (27% decrease at 32 h). This, however, does not
account for the delayed, potent inhibitory effect (76% decrease at
32 h; Fig. 4B) of IFN on the POMC 5'-promoter activity.
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, or IFN for
24 h. All cytokines except TNF significantly stimulated ACTH
secretion, among which IL-1ß showed the most potent effect (Table 1). Interestingly, IFN, which exerted
a long term suppressive effect on POMC expression, still acted
positively on ACTH release.
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on POMC expression were examined. CRH (100
nM; 3 h) showed a potent stimulatory effect on POMC
5'-promoter activity (1.9- to 2.1-fold increase), whereas each
cytokine alone (IL-1ß, IL-6, or TNF) had a minimal effect (7.3%,
8.4%, and 3.8% increases, respectively; Table 2). In contrast, when each cytokine was
simultaneously used with CRH, it markedly potentiated the increments
produced by CRH (59.0%, 41.1%, and 45.7% increases,
respectively).
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), the effects of
IL-1ß on forskolin- or 8Br-cAMP-induced POMC gene expression were
examined. Forskolin (10 µM; 3 h) and 8Br-cAMP alone
(5 mM; 3 h) showed potent stimulatory effects on the
POMC 5'-promoter activity (3.4- and 3.9-fold increases,
respectively), whereas IL-1ß alone again had minimal effects
(7.6–12.9% increase; Table 3). When
IL-1ß was simultaneously used with forskolin or 8Br-cAMP,
however, it potently enhanced the increments they produced (57.1% and
45.4% increase, respectively), just as IL-1ß potentiated the effect
of CRH.
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and partially eliminated the effect of IL-1ß (Fig. 5). In contrast, the effects of IFN
and IFN were not influenced by pretreatment with genistein (Fig. 6).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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also had short term effects in potentiating
the effect of CRH. Furthermore, we found that the tyrosine
phosphorylation cascade is involved at least partly in the
intracellular signaling of IL-1ß, IL-6, and TNF in corticotroph
cells.
The effect of IL-1 on ACTH secretion has been extensively studied both
in vitro and in vivo, showing an effect via the
hypothalamus (9, 10, 11, 12) and/or a direct effect on the corticotroph of the
anterior pituitary (13, 14, 15). IL-1 may also modulate cortisol secretion
at the adrenal cortex (16). There are some reports indicating that IL-1
increases POMC mRNA in vivo (17) or in vitro both
in the primary culture of rat anterior pituitary cells (18) and in
AtT20 cells (19). Our data obtained in this study clearly show that
IL-1ß stimulates POMC gene expression by acting on the POMC
5'-promoter. As has been reported for its effect on ß-endorphin
secretion (20), the dominant effect of IL-1ß on POMC expression
appeared very late (16 h or later), in contrast to the effect of CRH,
which was much faster (3 h) (5), suggesting that the mechanisms of
action of CRH and IL-1ß are different. The delay in the effect of
IL-1ß may be caused by the indirect mechanism of action, such that
IL-1ß induces the expression of de novo protein(s) such as
transcription factor(s), which, in turn, secondarily exerts a positive
effect on POMC gene expression. Interestingly, however, our short term
time-course study showed that IL-1ß also has an acute stimulatory
effect on POMC expression. Although the magnitude of the short term
effect of IL-1ß alone was very weak, it markedly enhanced the effect
of CRH when used simultaneously, suggesting the cooperative interaction
between CRH and IL-1ß at the corticotroph level. This amplifying
effect of IL-1 was reported previously for CRH-induced ß-endorphin
secretion (20). As corticotroph cells in the anterior pituitary as well
as AtT20 cells have a specific receptor for IL-1ß (21, 22), and the
minimal effective concentration of IL-1ß is fairly low (1
pM), we assume that blood-borne IL-1ß can directly
influence the expression of the POMC gene when the immune system is
activated during infectious stress.
We did not show any effect of IL-2 on the POMC 5'-promoter activity. IL-2 is reported to stimulate ACTH secretion and/or POMC expression both in vivo (23, 24, 25) and in vitro using primary culture of anterior pituitary cells (26) in the rat. On the other hand, Fukata et al. (15) showed no effect of IL-2 on ACTH secretion in AtT20 cells. Thus, it may be possible that IL-2 is acting on ACTH synthesis and secretion not directly on corticotroph cells, but, rather, indirectly through another factor(s) derived from a different cell population of the pituitary gland.
IL-6 has been shown to stimulate ACTH secretion at both hypothalamus
and pituitary (15, 27, 28, 29, 30). The effect of IL-6 on POMC gene expression,
however, has not yet been examined. Our data clearly show that IL-6 has
a long term monophasic stimulatory effect on POMC 5'-promoter activity.
Furthermore, like IL-1ß, short term treatment of IL-6 enhanced the
effect of CRH. However, the dose-response study revealed that a
relatively high concentration of IL-6 (1 nM) was needed
to produce this effect, raising the possibility of local action of the
cytokine. In fact, a recent study reports that IL-6 is produced within
the anterior pituitary by folliculostellate cells (31). IL-6 is also
secreted in the middle lobe of the pituitary by stimulation with
lipopolysaccharide or IL-1ß (32). Thus, these reports as well as our
data suggest that IL-6 may be acting on the corticotroph cells via
paracrine, rather than endocrine, mechanisms.
Previous reports concerning the effects of TNF on ACTH secretion
have shown that it stimulates the release of the hormone in
vivo (33, 34) but not in vitro (14, 33, 35, 36),
suggesting that the main effect is via the hypothalamus. Recently,
however, Kobayashi et al. (37) showed that TNF increases
POMC mRNA in AtT20 cells, suggesting a direct effect at the pituitary
level as well. We extended their finding by showing that TNF
stimulates POMC 5'-promoter activity in the corticotroph. The effect
was similar to that of IL-1ß, i.e. consisting of both
short and long term biphasic effects and occurring at a low
concentration (10 pM), suggesting that both cytokines may
partly if not totally share similar mechanisms of action. The acute
amplifying effect on CRH action was also observed with TNF. However,
the magnitude of the long term effect was much weaker (1.3-fold
increase) than that of IL-1ß, and this may be the reason why the
effect of TNF on ACTH synthesis/secretion at the pituitary level has
been missed in previous studies.
The effects of IFNs on ACTH synthesis and secretion remain
controversial; IFN (either IFN or IFN) is shown to stimulate ACTH
release in humans (38, 39, 40) but to inhibit it in rats in
vitro (35, 41). The effects of IFNs on the POMC gene in
corticotroph cells have not been previously reported. Our results
showed that both IFN and IFN had acute weak stimulatory effects
followed by potent inhibitory effects on POMC 5'-promoter activity,
which is quite different from the effects of other cytokines studied in
this report. As the POMC 5'-promoter sequence used here contains both
an IFN-stimulated response element and an IFN activation site (42),
the acute positive effect is supposed to be caused via direct
activation of transcription through the Janus kinase (JAK)/signal
transducers and activators of transcription (STAT) pathway (42). The
delayed inhibitory effect, on the other hand, may be caused indirectly
by some other de novo protein(s) induced by IFNs. In any
event, the effects of IFNs are unique among the cytokines tested, and
further studies are necessary, especially from the physiological
standpoint, to clarify why IFNs, which are known to be generated during
viral infection, are acting negatively on POMC gene expression, at
least at the pituitary level.
Our data showed that all cytokines except TNF significantly
stimulated ACTH release. The magnitude of the effect was largely
proportional to that on POMC promoter activity, except for that of IFN
(IFN), in which ACTH release was increased despite inhibition of
POMC expression. However, the IFNs had short term stimulatory effects
on promoter activity and probably exerted acute ACTH release as well,
in accordance with previous in vivo data (38, 39, 40). The lack
of a positive effect of TNF on ACTH secretion may simply be due to
its weaker potency.
It is of interest that whereas the short term effects of IL-1ß, IL-6,
and TNF by themselves on POMC 5'-promoter activity were very
subtle, they had hidden effects, such that they markedly potentiated
the stimulatory effect of CRH on POMC expression, as had been reported
for IL-1-induced ß-endorphin secretion (20) or in leukemia inhibitory
factor-induced POMC expression (43). The data suggest that these
cytokines somehow amplify the positive effect of CRH at some point(s)
of their signal transduction pathways. With regard to this issue, Takao
et al. (44, 45) recently showed that CRH up-regulates
IL-1ß receptors both in vivo and in vitro
(AtT20 cells). More recently, Pozzoli et al. showed that
IL-1ß increases CRH receptor mRNA in vitro (AtT20 cells),
suggesting the cooperative effect occurring at the receptor level (46).
However, a previous report showing that IL-1ß did not enhance
CRH-induced cAMP generation (20) and our finding that IL-1ß
potentiated forskolin- or 8Br-cAMP-induced POMC gene expression suggest
that the site of action of IL-1ß is at least in part distal to cAMP.
As IL-1 was shown to induce early protein phosphorylation in AtT20
cells (47), there may be some positive cross-talk effects in the
process of intracellular signaling pathways after the receptor level.
This cross-talk may also be the case with IL-6 and TNF, because
similar enhancing effects with CRH were observed in these two
cytokines. Thus, it may be possible that some cytokines have, in
addition to direct long term effects, short term modulatory effects on
hypothalamic factor-regulated POMC gene expression and form a dynamic
positive cooperativeness between immune and endocrine systems at the
molecular level within the pituitary gland.
Although the intracellular signaling pathways of cytokines have been
under extensive investigation (4), signal transduction within the
corticotroph cells largely remain to be clarified. Recently, Gwosdow
et al. showed that IL-1 stimulates the protein kinase A
pathway without increasing cAMP generation in AtT20 cells (48, 49), but
the mechanism mediating the effect is not known. As most of the
intracellular signaling pathways of various cytokines are mediated
through phosphorylation cascades (4), it seems likely that the same
mechanism is applicable to the corticotrophs. Our data, as expected,
showed that the long term positive effects of IL-1ß, IL-6, and TNF
were completely or partially eliminated by pretreatment of cells with
genistein, a broad spectrum inhibitor of protein tyrosine kinase and
several other kinases (50, 51). Interestingly, however, whereas the
effects of IL-6 and TNF were completely abolished by genistein
treatment, the effect of IL-1ß was only partially eliminated.
Furthermore, the negative effects of IFN and IFN were genistein
insensitive. Thus, it seems that the effect of each cytokine is
mediated through independent intracellular signaling pathways, and
further research is necessary to clarify this issue. In this sense, our
in vitro experimental system may be a good model to examine
the cellular and/or molecular mechanisms of cytokines on POMC gene
expression in corticotroph cells.
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Acknowledgments |
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Footnotes |
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Received October 16, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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