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Cedars-Sinai Research Institute, UCLA School of Medicine, Los Angeles, California 90048
Address all correspondence and requests for reprints to: Dr. Shlomo Melmed, Academic Affairs, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Room 2015, Los Angeles, California 90048. E-mail: melmed{at}csmc.edu
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-11R 2, differ in their 5'-untranslated
region (11, 12, 13). The human IL-11 receptor shows 83% protein homology
to the murine IL-11R (14, 15, 16), whereas there is no evidence for a
second IL-11R locus in the human analogous to the murine IL-11R 2
(15). Interleukin-11 (IL-11), as leukemia inhibitory factor (LIF),
interleukin-6, oncostatin M, ciliary neurotrophic factor and
cardiotropin-1, acts through a specific class I cytokine receptor using
the common gp130 signal transducer (1, 11, 14, 17). Although pituitary function is classically regulated by hypothalamic releasing hormones, several cytokines have been shown to play an important role in neuro-immuno-endocrine cross-talk for controlling hypothalamo-pituitary-adrenal (HPA)-function (18, 19, 20, 21). Recently, we have shown LIF to be an important activator of the HPA axis (21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31). LIF and LIF receptors are expressed in human and murine pituitary tissue (22, 23, 24). POMC gene expression and ACTH secretion are induced by LIF (22, 24, 25), and LIF induced ACTH secretion is mediated by the JAK-STAT pathway (26, 27, 28), and controlled in a negative feedback loop by the recently described SOCS-3 (suppressor of cytokine signaling) (27). Pituitary LIF expression is induced in mice in response to lipopolysaccharide endotoxin (23), and IL-1 (24). LIF knockout mice exhibit an attenuated HPA axis response to stress (29) and IL-1 (24), whereas transgenic mice overexpressing LIF by pituitary-targeted promoters exhibit pituitary corticotroph cell hyperplasia and hypercortisolism, with otherwise impaired pituitary function (30, 31).
Coadministration of IL-1 and IL-11 in mice increased corticosterone levels significantly higher than IL-1 alone (32). As ACTH levels were not measured in this study, no conclusions could be drawn with respect to the site of IL-11 action in the HPA axis. The aim of this study was to elucidate the role of IL-11 in pituitary corticotroph function. Here, we report IL-11 and IL-11R expression in normal human pituitaries and in pituitary adenomas, as well as in murine pituitaries and corticotroph AtT-20 cell line. We show stimulation of ACTH secretion, POMC gene expression, and POMC promoter activity by recombinant murine (rm)IL-11. In addition, we observed a negative feedback inhibition of IL-11 induced ACTH secretion by the suppressor of cytokine signaling protein SOCS-3. Thus, IL-11 effects the HPA axis similarly to LIF, providing further evidence for a redundant cytokine network in the neuro-immuno-endocrine regulation of the HPA axis.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Tissues
Male C57BL/6 mice were purchased from Jackson Laboratories at
the age of 8 weeks. After decapitation, tissues were immediately
removed and snap-frozen in liquid nitrogen. All experimental procedures
were approved by the Institutional Animal Care and Use Committee.
Postmortem normal human pituitaries were obtained from the Brain and Tissue Bank for Developmental Disorders (University of Maryland, Baltimore, MD). Specimen samples of corticotroph and nonfunctioning pituitary adenomas were obtained at transsphenoidal surgery.
Tissues were homogenized, followed by total RNA extraction with TRIZOL.
Cell culture
Cell culture of AtT-20/D16v-F2 cells was performed as described
(24). Briefly, for ACTH secretion, 1 x 104 AtT-20
cells were seeded in 48-well plates and grown for 48 h. After
serum-depletion (medium with 1% FBS) for a further 48 h,
treatments were added with fresh serum-depleted medium. After 24
h, the supernatants were collected and ACTH was measured with a
commercial RIA (Diagnostic Products Corp., Los Angeles,
CA). For RNA extraction, AtT-20 cells were seeded in 100-mm dishes at a
density of 1 x 106 cells and grown for 48 h.
After serum-free (medium with 0.1% BSA) incubation for a further
16 h, treatments were added with fresh serum-free medium. At the
timepoints indicated, total RNA was extracted using TRIZOL.
Several individual clones of SOCS-3 overexpressing AtT-20 cells (AtT-20S) and mock-transfected AtT-20 cells (AtT-20M) were obtained after stable transfection, as recently described (27). Three separate individual clones with high overexpression of SOCS-3 were chosen for the experiments.
Northern blot analysis
Northern blot analysis were performed as described (24, 27).
Briefly, 5–25 µg of total RNA were electrophoresed on a 1% agarose,
6.4% formaldehyde gel, and transferred to a nylon membrane and
hybridized with specific (-32P)CTP-labeled probes.
Probes were labeled with (-32P)CTP and Klenow enzyme
using random primer labeling with RadPrime. Prehybridization and
hybridization were performed using QuickHyb Rapid from
Stratagene, according to the manufacturers
recommendations. Autoradiographs were exposed to Kodak
Biomax MS film at -70 C.
Templates for probes
A 588-nucleotide (nt) fragment of the murine IL-11R
complementary DNA (cDNA) was generated as described below. The murine
SOCS-3 probe template was a PCR-generated cDNA fragment (19–610 bp;
GenBank accession number U88328), as described (27). The PCR products
were electrophoresed on an agarose gel and specific bands gel-purified
by Quiaex II. Before using as a template for random priming, the
specificity of each RT-PCR product was verified by multiple restriction
enzyme analysis. A 0.6-kb fragment of the murine POMC cDNA, encoding
the 3' half of exon 3 of the murine POMC gene was kindly provided by
Dr. Malcolm J. Low (Portland, OR). The ß-actin DECAprobe template was
the 1.076-kb fragment of the mouse ß-actin gene.
RT-PCR
DNase I digestion of total RNA samples was followed by RT with
Superscript I, performed according to the manufacturer’s instructions.
"Hot-start" PCR with Ampliwax PCR Gem 100 and Taq DNA
polymerase was performed on a GeneAmp PCR System 9600, using a final
MgCl2 concentration of 1.5 mM. Each PCR
reaction consisted of an initial denaturation step (94 C, 3 min),
followed by 40 cycles (denaturation 94 C, 30 sec; annealing 58 C, 30
sec; extension 72 C, 45 sec) and a single elongation step at 72 C for
10 min. DMSO at a final concentration of 5% was added, when
appropriate.
A 588-nt fragment of the murine IL-11R cDNA (nt 304–891, GenBank
Accession UU14412), spanning exon 4 to exon 9 was generated with a
primer pair, common to the murine IL-11R and IL-11R 2 locus.
Specific cDNA fragments of the murine IL-11R isoform (nt 23–535,
GenBank Accession U14412) and the murine IL-1R 2 isoform (nt
281–792, GenBank Accession U69491) were obtained by using different
specific sense primers in the untranslated 5'-messenger RNA (mRNA)
region of each receptor locus and a common antisense primer,
recognizing both loci. A 565-nt fragment of the murine IL-11 cDNA (nt
200–764, GenBank Accession U03421) was created with specific primers,
using an annealing temperature of 60 C.
Specific primers for the human IL-11R resulted in a 710 nt cDNA
fragment (nt 191–901, GenBank Accession U32324), spanning exon 3 to
exon 9. A primer pair in exon 5 of the human IL-11 gene was used to
amplify a 322 nt PCR product (nt 709-1030, GenBank Accession M57765).
All primer sequences are shown in Table 1
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Hormone assays and statistical analysis
Statistical analysis was performed by unpaired t
test. All values are mean ± SE.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-11R 2, an expected band of 588 nt was
detected by RT-PCR in total RNA derived from testis (positive control),
pituitary and corticotroph AtT-20 cells (Fig. 1A, lane 1). Restriction enzyme digestion
with NcoI resulted in expected fragments of 288 and 300 nt
length. To discriminate between the two receptor isoforms, sense
primers specific for the different untranslated 5'-regions of each
receptor isoform were used together with a common antisense primer in
the highly homologous coding sequence of both isoforms. Expected
bands of 512/511 nt for the IL-11R (Fig. 1A, lane 2) and IL-11R
2 (Fig. 1A, lane 3) isoform, were observed in testis and pituitary,
respectively. In contrast, in AtT-20 cells only IL-11R , but not
IL-11R 2 mRNA was detected. Restriction enzyme digestion with
MspI resulted in expected fragments of 169/168 and 343 nt
length, respectively. Although all primer pairs were chosen to span
several exons, RT negative controls of each sample were run in every
PCR and did not yield a product (data not shown). Northern blot
analysis of 25 µg total RNA from different tissues was performed with
a PCR-created probe spanning exon 5 to 9 of the murine IL-11R,
detecting both receptor isoforms. IL-11R mRNA was detectable by
Northern blot in all examined tissues; however, the level of expression
varied widely (Fig. 1B). When testing the tissue components of the HPA
axis, pituitary and adrenal showed abundant IL-11R mRNA expression,
whereas hypothalamic IL-11R mRNA expression was less marked. IL-11R
mRNA expression was also detectable by Northern blot in corticotroph
AtT-20 cells, although with lower abundance, than in the normal
pituitary (Fig. 1B).
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). Restriction enzyme digestion with ApaI resulted in
expected fragments of 228 and 337 nt length.
IL-11 and IL-11 receptor mRNA expression in the normal human
pituitary and pituitary adenomas
Using RT-PCR, gene expression of human IL-11R and IL-11 was
detected in total RNA derived from normal pituitaries (n = 3),
corticotrophic adenomas (n = 2), and nonfunctioning adenomas
(n = 2) (Fig. 2, A and B). Specific
primers for the human IL-11R amplified an expected product of 710 nt.
Restriction enzyme digestion with BamHI resulted in
fragments of 388 and 322 nt length (Fig. 2A). Specific primers for
human IL-11 amplified an expected product of 322 nt. IL-11 expression
was barely detectable after 40 PCR cycles, with the exception of the
second corticotroph adenoma, which showed a stronger band. Restriction
enzyme digestion with BglII resulted in fragments of 256 and
66 nt length (Fig. 2B). RT negative controls for each sample did not
reveal a PCR product.
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). In comparison to IL-11, LIF was a
more potent stimulus of ACTH secretion from AtT-20 cells. At
concentrations from 10-11 to 10-9
M LIF induced ACTH secretion 1.4 ± 0.11, 1.6 ±
0.11 and 1.5 ± 0.06-fold, respectively (Fig. 3). At equimolar
concentrations of 10-11 M (P
< 0.05) and 10-10 M (P <
0.01), LIF induced significantly higher concentrations of ACTH in
comparison to IL-11. Coincubation of LIF with IL-11 at the maximal
concentration of 10-9 M resulted in higher
ACTH levels than LIF alone (P < 0.05) (Fig. 3).
However, this apparent interaction of LIF and IL-11 on ACTH secretion
might also be accounted for by the slightly lower-fold stimulation of
ACTH by LIF alone.
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). Similarly,
LIF (0.5 x 10-9 M) or the combination of
IL-11 and LIF (0.5 x 10-9 M, each)
caused a 1.7 ± 0.013 (P < 0.01) and 1.8 ±
0.16-fold (P < 0.01) increase of POMC mRNA,
respectively (Fig. 4).
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). LIF (0.5 x 10-9
M) and Bu2cAMP (5 mM) caused an
3.7 ± 0.15 and 7.1 ± 0.52-fold increase of POMC promoter
activity, respectively (P < 0.001). POMC promoter
activity was stimulated in an additive manner by LIF plus IL-11 to
4.5 ± 0.16-fold vs. control (P <
0.001 vs. LIF alone). Bu2cAMP plus IL-11
resulted in a synergistic stimulation of POMC promoter activity to
11.7 ± 0.71-fold vs. control (P <
0.001 vs. Bu2cAMP alone) (Fig. 5).
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). A lower concentration of IL-11
(0.5 x 10-11 M) had no significant
effect on SOCS-3 expression (data not shown).
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). IL-11 alone (10-9
M) stimulated ACTH levels 1.5 ± 0.09-fold in AtT-20M
cells, whereas in AtT-20S cells there was only an increase to 1.1
± 0.04-fold over control (P < 0.01 AtT-20M
vs. AtT-20S). In contrast, Bu2cAMP (2.5
mM) significantly increased ACTH levels in both, AtT-20M
and AtT-20S cells, to a similar extent (1.5 ± 0.12 and 1.4
± 0.06-fold). In comparison to Bu2cAMP alone, incubation
of cells with Bu2cAMP plus IL-11 resulted in enhanced
induction of ACTH secretion in AtT-20M cells (2.1 ± 0.21-fold;
P < 0.05) but not in AtT-20S cells (1.6 ± 0.06;
n.s.) (Fig. 7).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). Expression of mIL-11 mRNA
has been found to be very low in most other tissues examined and not
detectable by Northern blot analysis or RNase protection assay (7, 10, 33). Using Northern blot analysis, we found an expected 1.8-kb
transcript for mIL-11R mRNA (34) in hypothalamus, pituitary, and
adrenal (Fig. 1B). mIL-11R mRNA was abundantly expressed in murine
hypothalamus, pituitary, and adrenal, and to a lesser extent also in
AtT-20 cells. Two distinct loci for the mIL-11R, mIL-11R and
mIL-11R 2 show 99% nucleotide identity of the coding sequence
spanning exon 2 to 13 (12, 13, 34). Receptors expressed by both mIL-11R
gene loci have been found to have similar binding properties for mIL-11
(13), whereas the functional properties of the mIL-11R2 are not yet
characterized (13). Our 588-nt probe spanning exon 4 to 9 did not
distinguish the two different receptor loci in Northern blot analysis.
We discriminated mIL-11R and mIL-11R 2 gene expression by
RT-PCR, using different sense primers, located in the specific
5'-untranslated region of each locus, namely the untranslated exon 1a
of mIL-11R (nt 23–43, GenBank Accession X94162) and untranslated
part of exon 2 of mIL-11R 2 (nt 3461–3480, GenBank Accession no.
U69492), respectively. The mIL-11R locus itself encodes two
different transcripts, mIL-11R a and mIL-11R b, caused by
different splicing of untranslated exons 1a and 1b to exon 2 (13, 34).
mIL-11R b might only be expressed in embryonic tissues, whereas
mIL-11R a is the transcript form present in adult tissues (34). The
antisense primer, common for the mIL-11R and mIL-11R 2 locus,
was specific for a sequence overlapping exon 6/7 junction of both
mIL-11R loci (nt 4825–4833/4941–4952, GenBank Accession X95162; NT
749–757/836–847, GenBank Accession X94158), respectively. Using this
approach, in the pituitary of C57BL6 mice mIL-11R and mIL-11R 2
gene expression was detected. In contrast, in the corticotroph cell
line AtT-20, only mIL-11R , but not mIL-11R 2 gene expression,
could be shown (Fig. 1B). As the mIL-11R 2 locus is not present in
all mouse strains (34), the lack of mIL-11R 2 gene expression in
AtT-20 cells might be caused by strain differences. Another possibility
would be that corticotroph cells express only the mIL-11R gene,
whereas other cells account for pituitary mIL-11R 2 gene
expression.
Using RT-PCR, we also demonstrated IL-11 and IL-11R gene expression in
human normal pituitaries, as well as in corticotroph and nonfunctioning
pituitary adenomas (Fig. 2). These findings are in accordance with a
recent preliminary study (35), also reporting IL-11 and IL-11R mRNA
expression in normal human pituitaries and corticotroph adenomas. As we
also found nonfunctioning pituitary adenomas to be positive for IL-11
and IL-11R mRNA, the corticotroph cell seems not to be the only
pituitary cell expressing IL-11 and its receptor. By
immunohistochemistry, we previously have observed a widespread
expression of LIF and its receptor in the human fetal pituitary,
although most frequently expressed in corticotroph and somatotroph
cells (22). Further studies using in situ hybridization and
immunohistochemistry are requested to reveal, whether a similar
expression pattern is also present for IL-11 and its receptor in the
human pituitary.
In the murine corticotroph cell line AtT-20, we found that IL-11
stimulates ACTH secretion, POMC gene expression, and POMC promoter
activity. IL-11 stimulated ACTH secretion alone and in modest synergy
with Bu2cAMP (Figs. 3 and 7). Similarly, LIF induces ACTH
secretion alone and in synergy with CRH (36). While these data are
highly suggestive of a synergistic effect between IL-11 and cAMP on
ACTH secretion, a partial action of Bu2cAMP being mediated
by butyrate rather than the cAMP component cannot be totally excluded.
Coincubation of IL-11 with LIF showed a modestly induced ACTH secretion
and POMC gene expression in comparison to LIF alone. As both cytokines
act through the common gp130 receptor subunit, LIF and IL-11 might
compete for gp130 after ligand binding of either cytokine to its
respective receptor. This assumption might be the limiting step,
preventing a pronounced additive effect of IL-11 with LIF. Comparing
the potency of IL-11 and LIF as stimulators of ACTH secretion in
vitro, IL-11 appears less effective than LIF. While the lowest
concentration of IL-11, which significantly induced ACTH secretion
in vitro was about 10-10 M, LIF was
also effective at lower concentrations. During incubation with
equimolar concentrations of either cytokine, LIF appeared to be a more
potent stimulator of the corticotroph cell in comparison to IL-11.
Systemic injection of IL-11 synergistically stimulates IL-1 induced
corticosterone levels in mice in vivo (32). Only limited
information on serum levels of IL-11 in inflammation and sepsis are
available (37, 38). IL-11 serum levels have been reported to be
nondetectable in patients with different rheumatic diseases (37). In
patients with disseminated intravascular coagulation and sepsis, about
66% showed measurable IL-11 serum levels with a mean value of 20 pg/ml
(38). Based on these limited number of studies (37, 38), circulating
IL-11 seems not to be widely regulated by inflammatory disease states.
However, numerous studies have demonstrated local expression of IL-11
to be stimulated by the inflammatory cytokine IL-1 in various cell
types (for review, see Ref. 2). We have previously shown local LIF gene
expression in the pituitary in vivo to be stimulated by
lipopolysaccharide endotoxin (23) and IL-1ß (24), suggesting that
IL-6 cytokine family members are important auto/paracrine mediators of
HPA axis activation in response to inflammatory stimuli. Using Northern
blot technique, we could not detect a signal for IL-11 in untreated and
IL-1ß stimulated AtT-20 cells (data not shown), although IL-11 mRNA
was detectable in AtT-20 cells by RT-PCR (Fig. 1C). As the expression
level of IL-11 mRNA is very low in most tissues (7, 10, 33), further
studies using RNase protection assay or semiquantitative PCR should
evaluate a possible local regulation of IL-11 gene expression in
hypothalamus or pituitary. While our results were obtained using the
corticotroph AtT-20 cell line, studies using primary cell culture
models might provide additional insight into the role of IL-11 in
pituitary function and help understand its physiological relevance.
A family of suppressor of cytokine signaling (SOCS) proteins has been
recently described (39, 40, 41). Expression of SOCS proteins is inducible
by different cytokines and SOCS-1 has been shown to block the Jak-STAT
signaling cascade by inhibiting the enzymatic activity of JAK kinases
(39, 40, 41). Recently, we showed pituitary SOCS-3 expression to be
stimulated by LIF, and SOCS-3 acting as a negative feedback regulator
for LIF-induced ACTH secretion and POMC gene expression, by inhibiting
gp130 and Stat-3 phosphorylation (27). Herein, we now show IL-11 to
stimulate SOCS-3 gene expression in corticotroph AtT-20 cells (Fig. 6).
Similar to the effects observed on ACTH secretion and POMC expression,
on an equimolar basis, IL-11 was less potent than LIF in stimulating
SOCS-3 (data not shown). Overexpression of SOCS-3 in AtT-20 cells
resulted in significant inhibition of IL-11 stimulated ACTH secretion
(Fig. 7). This finding is compatible with the known signaling mechanism
of IL-11 in other cell systems, involving gp130 phosphorylation,
and Jak/STAT activation (1, 2, 11, 14, 42).
In summary, we have found IL-11 and IL-11 receptor mRNA to be expressed in murine hypothalamus, pituitary, and the corticotroph cell line AtT-20. Expression of IL-11 and IL-11 receptor mRNA could also be demonstrated by RT-PCR in human normal pituitaries, as well as corticotrophic and nonfunctioning pituitary adenomas. We have shown for the first time that IL-11 stimulates ACTH secretion, POMC gene expression, and POMC promoter activity in AtT-20 cells. Furthermore, IL-11 induces gene expression of SOCS-3 in AtT-20 cells, whereas SOCS-3 exerts an inhibitory effect on IL-11 induced ACTH secretion, indicating a negative regulatory feedback mechanism of SOCS-3 on IL-11 signaling. In comparison to LIF, IL-11 appears to be a less potent stimulator of the corticotroph cell in vitro. Further studies, using in vivo and primary in vitro models, are requested to evaluate the physiological role of IL-11 in HPA axis regulation. As IL-11 affects the HPA axis similarly to LIF, these results provide further evidence for a redundant cytokine network in the neuro-immuno-endocrine regulation of the HPA axis.
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Footnotes |
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Received July 21, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-chain
gene (IL11R2) with a restricted pattern of expression. Genomics 40:387–394[CrossRef][Medline]
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-chain and a related locus. J Biol Chem 271:13754–13761This article has been cited by other articles:
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