Cedars-Sinai Research Institute-University of California Los Angeles School of Medicine, Los Angeles, California 90048
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ABSTRACT |
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We have shown that leukemia
inhibitory factor (LIF) and suppressor of cytokine signaling (SOCS)-3
are expressed in the hypothalamus and pituitary and that LIF induces
proopiomelanocortin (POMC) and ACTH, whereas SOCS-3 abrogates
corticotroph POMC gene transcription and ACTH secretion. Here, we
determined the role of pituitary LIF and SOCS-3 in regulating
hypothalamo-pituitary-adrenal (HPA) axis inflammatory responses.
Murine pituitary LIF expression was induced up to eightfold after
intraperitoneal injection of lipopolysaccharide or tumor necrosis
factor-, concordant with elevated plasma levels of ACTH and
corticosterone. In LIF knockout (LIFKO) mice, induction of both ACTH
and corticosterone were attenuated. LIF deletion was associated with
elevated (P < 0.05) levels of pituitary TNF-
, interleukin (IL)-1
, and IL-6 mRNA and cytokine-inducible pituitary SOCS-3 expression. Abrogation of the HPA axis stress response and
higher pituitary levels of proinflammatory cytokines observed in LIFKO
mice resulted in a stronger inflammatory process, as evidenced by
elevated erythrocyte sedimentation rate and increased serum amyloid A
levels (P < 0.05). The results indicate that, although
LIF induces ACTH, SOCS-3 acts to counterregulate the HPA axis response
to inflammation.
hypothalamo-pituitary-adrenal axis; suppressor of cytokine signaling-3; inflammation
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INTRODUCTION |
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CYTOKINE REGULATORS of immune and inflammatory processes play important roles in activating hypothalamo-pituitary-adrenal (HPA) axis responses to immunological challenges. Cytokines are locally produced at the site of inflammation, and circulating plasma cytokine levels are elevated as a result of systemic inflammation. Lipopolysaccharide (LPS) administration or inflammation also induces hypothalamic and pituitary cytokines, which centrally activate the HPA axis inflammatory stress response (6, 21, 28, 29, 37).
Leukemia inhibitory factor (LIF), a member of the interleukin (IL)-6 cytokine family, is a pleiotropic cytokine with diverse biological activity (26). LIF is increased in a variety of inflammatory conditions, including rheumatoid arthritis and septic shock (40, 41). Prior LIF administration protects against lethality during endotoxemia in mice in a dose- and time-dependent manner (40). LIF also plays an important role in the development and functioning of the HPA axis (42). LIF and LIF receptor are constitutively expressed in human pituitary cells (30) and in murine hypothalamus and pituitary (39). LIF regulates differentiation and development of murine pituitary corticotrophs early in ontogenesis (29), potently induces proopiomelanocortin (POMC) gene transcription and ACTH secretion (2, 30), and potentiates corticotropin-releasing hormone (CRH) induction of POMC gene expression (11, 13). In vivo, LIF along with CRH maintains POMC expression and ACTH secretion in response to emotional stress (14).
Corticotroph cell-signaling pathways for the IL-6 cytokine family involve heterodimerization between cytokine receptor and gp130 receptor subunits with subsequent Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway activation (10, 30) and induction of cytokine-inducible suppressor of cytokine signaling (SOCS)-3 (5, 35). We demonstrated in vivo pituitary SOCS-3 induction by proinflammatory cytokines (5). In AtT20 corticotroph cells, SOCS-3 overexpression inhibits cytokine-stimulated gp130 and STAT3 phosphorylation, ACTH secretion, POMC mRNA expression, and POMC promoter activity (5, 10, 12). SOCS-3 thus behaves as an intracellular negative feedback mediator of the cytokine-endocrine interface.
Several lines of evidence support the role for hypothalamic-pituitary
LIF in the chronic inflammatory process. Earlier, we demonstrated that
LIF was induced almost exclusively in the hypothalamus in response to
chronic systemic inflammation stimulated by mycobacterial adjuvant and to chronic local inflammation produced by intramuscular turpentine administration. In both inflammatory models, LIF-deficient mice exhibit attenuated POMC, ACTH, and corticosterone responses to
inflammatory stimuli (14, 15). In the present study, we examined more closely mechanisms implicating central LIF in the neuroendocrine interface in acute, rapidly evolved, LPS-induced inflammation. The results show that pituitary LIF is strongly activated
in response to LPS and tumor necrosis factor (TNF)-. LIF knockout
(LIFKO) mice demonstrate lower corticosterone responses, thereby
promoting the inflammatory process. Pituitary cytokine overexpression
enhances cytokine-inducible pituitary SOCS-3, thus further suppressing
inflammatory ACTH responses in LIFKO mice. This study shows that
pituitary LIF and SOCS-3 are important for rapid regulation of the ACTH
axis during acute inflammation.
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METHODS |
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Animals.
Mice heterozygous for the disrupted LIF gene (LIFKO) were kindly
provided by Dr. Colin L. Stewart (Roche Institute of Molecular Biology,
Roche Research Center, Nutley, NJ). Because LIFKO females exhibit
defective blastocyst implantation, homozygous LIFKO animals were bred
by heterozygous or homozygous male and heterozygous female mating on a
B6D2F1 genetic background. After PCR DNA analysis (14) of
tail tissue, homozygous mice were sex and age matched with wild-type
(WT) litters. Animals were kept on a 0600-1800 daytime cycle with
free access to food and water and housed five per cage. Female mice,
8-14 wk of age were used for the experiments: LIF+/+, or WT normal, and LIF/
, or LIFKO,
mice. All experimental procedures were approved by the
Institutional Animal Care and Use Committee.
In vitro treatment. Pituitary corticotroph AtT20/D16v-F2 cells (American Tissue Culture Collection) were grown as described (15) in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum, 2 mM L-glutamine, 100 U/ml streptomycin, and 100 U/ml penicillin. Cells were pretreated with 5 µM murine SOCS-3 antisense (AS) or mismatch (MM) oligonucleotides (Molecular Research Laboratories, LLC, Herndon, VA) for 36 h. For the last 16 h, cells were incubated in serum-free DMEM. Thereafter, fresh serum-free DMEM, AS or MM with or without 25 nM murine IL-6 (R&D Systems, Minneapolis, MN), were added, and after 1 h, cells were harvested for RNA isolation.
RNA was analyzed for SOCS-3 by Northern blot analysis, and each membrane was washed and reprobed for POMC expression. Relative abundance of SOCS-3 mRNA was determined by densitometry and normalized to levels of POMC mRNA in the same sample: the POMC-to-SOCS-3 ratio was calculated, standardized in relation to the control values taken as 1, and presented as fold increase.In vivo treatment. Fifty micrograms of LPS (from Escherichia coli, stereotype 0111:B4, Sigma, St.Louis, MO) in 200 µl of normal saline were injected intraperitoneally into WT and LIFKO mice. Animals were killed 0.5, 1, 4, or 8 h after injection. For serum amyloid A (SAA) measurement, animals were injected with 80 µg of LPS and killed at 8 or 30 h after injection.
Murine TNF-Blood collection and hormone assay.
Whole blood was obtained immediately after decapitation, and plasma was
collected in ice-chilled tubes containing 0.1% EDTA, separated, and
stored at 70°C until assayed. Plasma ACTH (Nichols Institute
Diagnostics, San Juan Capistrano, CA) and corticosterone (ICN
Biomedicals, Costa Mesa, CA) were measured by commercially available
RIAs. Sensitivity of ACTH and corticosterone assays was 10 pg/ml and 25 ng/ml, respectively. Inter- and intra-assay variability for ACTH was
7.3 and 3.1%, respectively; inter- and intra-assay of variability for
corticosterone was 4.4 and 6.5%, respectively.
Erythrocyte sedimentation rate. Whole trunk blood was anticoagulated with EDTA and diluted 1:1 with sodium citrate. Erythrocyte sedimentation rate (ESR) was measured using Wintrobe 3 × 115-mm tubes (Becton-Dickinson, Franklin Lakes, NJ) filled up to 500 mm. Blood was obtained from untreated mice or animals killed 8 h after LPS injection, and measurements were made 16 h later.
SAA.
Trunk blood was collected from untreated and LPS-treated animals, serum
aliquoted, and stored at 20°C and SAA measured in 20 µl of serum
by commercial ELISA SAA assay kit (Hemagen, Waltham, MA) according to
the protocol.
Tissue dissection and RNA isolation.
Mice were decapitated and pituitary dissected, and tissue was
immediately frozen on dry ice and kept at 70°C until RNA
extraction. Total tissue RNA was extracted with TRIzol reagent
(GIBCO-BRL, Gaithersburg, MD) according to the manufacturer's
instructions, in which 5-100 mg of frozen tissue were immersed in
1 ml of TRIzol solution and homogenized with a Polytron homogenizer,
dissolved in diethyl pyrocarbonate water, and RNA concentration was
spectrometrically quantitated and quality checked by gel electrophoresis.
Northern blot analysis.
Northern analysis was performed using 2-25 µg of total RNA per
lane. Samples were electrophoresed through a 1% agarose gel containing
2.2 M formaldehyde and transferred to a nylon membrane (Nytran 228, Schleicher & Scheull, Keene, NH), membranes were ultraviolet
cross-linked, and blots were prehybridized in 1 M NaPO4,
20% SDS, and 0.1% BSA for 1 h at 65°C. 32P-labeled
specific probes (106 cpm/ml) were added and membranes
hybridized overnight at 65°C. Membranes were then washed in 2×
standard sodium citrate (SSC) and 0.1% SDS for 30 min, 1× SSC and
0.05% SDS for 30 min, 0.5× SSC and 0.025% SDS for 1 h, and
0.1× SSC and 0.005% SDS for 1 h at 65°C and exposed to Kodak
Biomax film for 2-4 h for POMC and 18S, 24-48 h for SOCS-3,
and 48-72 h for LIF mRNA at 70°C.
Plasmids and templates. Mouse 18S is a 1.212-kb plasmid insert (Mouse DECAprobe template; Ambion, Austin, TX). The EcoRI-XbaI fragment of the murine LIF complementary DNA (cDNA) spanning the entire coding sequence of murine LIF (2-631 bp; GenBank accession no. A01690; provided by Dr. Tracy Willson, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia) was cloned into a pcDNA3 vector, isolated, electrophoresed in 1.2% agarose gel, and extracted with Quiaex II. Murine SOCS-3 cDNA (19-610 bp; GenBank accession no. U88328; 20-bp primers) was isolated in our laboratory by RT-PCR of murine pituitary mRNA (5). Before use as a template for random priming, the specificity of the RT-PCR product was verified by multiple-restriction enzyme analysis. The 0.6-kb fragment of murine POMC cDNA, encoding the 3' half of exon 3 was kindly provided by Dr. Malcolm J. Low (Portland, OR). Probes were labeled by random priming with a Random Primer Labeling Kit (Stratagene, La Jolla, CA).
Relative RT-PCR. Total pituitary RNA was prepared as described, and, before the reverse transcription reaction, RNA samples were treated with DNase l (DNA-free DNase Treatment & Removal Reagents; Ambion) to eliminate DNA contamination. Total RNA (2.5 µg) was reverse transcribed into first-strand cDNA by use of a SuperScript Preamplification System (GIBCO-BRL) and random hexamers according to the manufacturer's protocol. Subsequent PCR reactions were performed using a GeneAmp PCR System 9600 (Perkin-Elmer, Norwalk, CT).
Relative levels of TNF-Statistical analysis. Data were analyzed using one-way analysis of variance within genotypes followed by nonparametric t-test (Mann-Whitney Test). A t-test was used for single comparisons between WT and LIFKO mice.
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RESULTS |
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Six to seven control animals were injected with sterile PBS and
killed 1, 4, or 8 h after injection. No changes were observed in
pituitary LIF, TNF-, IL-1
, IL-6, or SOCS-3 gene expression throughout the 8-h observation period. However, plasma corticosterone levels increased moderately (20%) 1 h after PBS injection, and by
4 h, corticosterone levels returned to normal. Therefore, with this nonspecific injection effect on plasma stress hormones levels taken into account and to limit the number of animals required, mice of
both genotypes were injected with PBS and killed 1 h after treatment and used as controls for each time point.
Time course of plasma ACTH and corticosterone levels after LPS
treatment.
After intraperitoneal injection of 50 µg of LPS, pituitary LIF mRNA
levels in WT mice were induced 9 ± 0.5-fold (P < 0.05) at 1 h and peaked (16 ± 2-fold, P < 0.05) 4 h after the inflammatory challenge (Fig.
1). The role of LIF in HPA axis
activation was assessed in WT and LIFKO mice for up to 8 h after
LPS injection. Plasma ACTH levels did not differ in WT and LIFKO
control mice (135 ± 35 vs. 87 ± 28 pg/ml, respectively). In
WT mice, ACTH levels increased at 1 h (from 135 ± 35 to
380 ± 72, not significant), peaked 4 h after injection
(630 ± 76 pg/ml, P < 0.01 vs. controls), and
remained elevated 8 h after LPS injection (480 ± 66 pg/ml, P < 0.05 vs. controls). In LIFKO animals, the time
course of the ACTH response differed. Plasma ACTH levels peaked 1 h after LPS treatment (718 ± 85 pg/ml, P < 0.01 vs. controls) and were actually higher than in WT animals
(P < 0.05) at this time. However, by 4 h, levels
had already dropped below those observed in WT mice (331 ± 56 vs.
630 ± 76 pg/ml, P < 0.5) and continued to
decline 8 h after injection (Fig.
2). Baseline levels of plasma
corticosterone were elevated in both genotypes after PBS treatment.
Circulating corticosterone levels in WT mice rose markedly starting at
30 min (from 350 ± 118 in controls to 998 ± 121 ng/ml,
P < 0.05) and continued to rise for up to 8 h
after LPS treatment (1,420 ± 188 ng/ml, P < 0.01 vs. controls). In LIFKO mice, although plasma corticosterone was
elevated above control levels at 1 h (659 ± 98 vs. 175 ± 54 ng/ml, P < 0.05), 4 h (770 ± 136 vs.
175 ± 54 ng/ml, P < 0.05), and 8 h
(882 ± 101 vs. 175 ± 54 ng/ml, P < 0.05) after injection, this elevation was lower (P < 0.05)
than in WT animals at the same times (Fig. 2).
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Pituitary cytokine gene expression.
Proinflammatory cytokines induced within the pituitary during the
course of inflammation are involved in activating the HPA axis
inflammatory response (37). A detectable transcript of pituitary IL-1 and TNF-
could be seen only after longer exposure of Northern blots (data not shown). Because of the low levels, IL-1
,
IL-6, and TNF-
cytokine gene expression in WT and LIFKO animals were
further analyzed by competitive RT-PCR. After LPS inoculation,
pituitary IL-1
mRNA levels increased more abundantly in LIFKO mice
at 1 h (81 ± 5 in LIFKO vs. 64 ± 7 in WT,
P < 0.05) and 8 h (32 ± 1 in LIFKO vs.
18 ± 3 in WT, P < 0.05) after treatment. A
similar pattern was noted for pituitary IL-6 gene expression, which was
induced further in LIFKO mice 1 h after endotoxin treatment (25 ± 2 in LIFKO vs. 15 ± 3 in WT, P < 0.05) (Fig. 3A). TNF-
induction was also higher in LIFKO animals (211 ± 9 in LIFKO vs. 94 ± 3 in WT, P < 0.05) (Fig. 3B).
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Pituitary SOCS-3 gene expression after LPS treatment.
SOCS-3 is an intracellular negative regulator of cytokine signaling in
pituitary corticotrophs. Considering the strong induction of
intrapituitary inflammatory cytokines observed in LIFKO mice, we
examined pituitary SOCS-3 expression. In WT mice, pituitary SOCS-3 mRNA
levels increased at 1 h (6 ± 0.6-fold, P < 0.05), peaked at 4 h (10 ± 1-fold, P < 0.05), and remained persistently elevated 8 h (9.1 ± 1-fold,
P < 0.05) after LPS injection compared with
control PBS-treated animals. In LIFKO mice, the time course of
pituitary SOCS-3 induction was similar. Pituitary SOCS-3 mRNA levels
increased at 1 h (9 ± 1-fold, P < 0.05),
peaked at 4 h (15 ± 1.0-fold, P < 0.05),
and remained higher at 8 h (13 ± 1-fold, P < 0.5). However, the overall increase of pituitary SOCS-3 gene expression was considerably stronger in LIF-deficient mice. Differences in SOCS-3 induction within the two experimental groups were greater at
4 h (15 ± 1.0-fold vs. 10 ± 1-fold, P < 0.05) and 8 h (13 ± 1-fold vs. 9 ± 1-fold,
P < 0.05) after treatment (Fig.
5).
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Relationship between SOCS-3 and POMC gene expression in vitro.
SOCS-3 appeared to play a critical role in inhibiting cytokine-mediated
POMC induction (5). To further investigate the physiological role of SOCS-3 in restricting pituitary POMC expression, levels of POMC and SOCS-3 mRNA abundance in the same experimental settings were examined in AtT20 mouse corticotrophs. IL-6 induces both
SOCS-3 and POMC gene expression in a timely manner (5). In
control cells treated with MM oligonucleotides, SOCS-3 was induced,
whereas POMC was abrogated 1 h after IL-6 treatment. Conversely,
pretreatment of AtT20 cells with SOCS-3 AS oligonucleotides suppressed
SOCS-3 mRNA levels with subsequent increased POMC expression. AS also
abrogated the SOCS-3 response to IL-6 (Fig.
6). The POMC/SOCS-3 mRNA ratio derived
from three independent experiments (Table
1) showed a negative
relationship between POMC and SOCS-3 gene expression.
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Inflammatory responses after LPS injection.
The impact of HPA axis activation on the severity of inflammation in
LIFKO animals was analyzed. Baseline ESR did not differ between the two
genotypes. After LPS injection, acceleration of the ESR was noted at
1 h, and in LIFKO mice, endotoxin-induced ESR was higher compared
with WT animals (22 ± 3 vs. 16 ± 1 mm, P < 0.05) at 16 h (Fig. 7).
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DISCUSSION |
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We show here that LIF is an important component of the cytokine
network regulating the neuroendocrine response to inflammation. Baseline pituitary LIF expression is very low in healthy,
inflammation-free animals and is induced in response to endotoxin
stimulation. Pituitary LIF gene activation could result from the
stimulatory effects of cytokines produced during systemic inflammation.
Our current in vivo results indicate that pituitary LIF induction is at
least partly stimulated by TNF- released in the course of endotoxic shock. Thus pituitary LIF mRNA levels increased significantly 1 h
after TNF-
treatment. We recently reported marked hypothalamic and
modest pituitary LIF induction in animals with chronic local inflammation (15). These results are in contrast to the
present finding that LIF is strongly induced in the pituitary after LPS treatment. LPS evokes acute inflammatory shock, resulting in high systemic levels of proinflammatory cytokines. LPS directly induces secretion of brain immunoregulatory cytokines that modulate their own
pituitary and peripheral levels (31). The pituitary is
exposed to circulating macrophages and peripheral cytokines, which may stimulate pituitary LIF expression in a paracrine or endocrine manner
(20, 21, 37). In contrast, a local inflammatory process does not increase high cytokine levels. The results suggest that, in
mice with local chronic inflammation, hypothalamic LIF is more likely
induced via prolonged stimulation of visceral afferents originating at
the site of inflammation.
When it is considered that LIF is a potent activator of pituitary POMC transcription and ACTH secretion (2, 7, 11, 14, 29), the induction of pituitary LIF gene expression could be an important component for HPA axis function during LPS-induced inflammatory stress. HPA responses were therefore compared in WT and LIFKO mice. Overall, LIF deficiency leads to blunting of the ACTH and corticosterone responses to inflammatory stress.
HPA stress response and glucocorticoids restrict the inflammatory
process mostly by inhibiting synthesis and release of proinflammatory cytokines (32, 33). A variety of hypothalamic and
pituitary cytokines and their receptors are constitutively expressed
and play an important role in modulating pituitary hormone secretion (16, 25, 29, 37). In these experiments, pituitary IL-1, IL-6, and TNF-
expression increased in response to inflammatory stress. Pituitary cytokines are to some extent also a component of the
peripheral cytokine pool. We therefore cannot exclude that circulating
stimulated immune cells (e.g., macrophages) residing in the pituitary
may contribute to the observed levels of pituitary cytokine messenger
RNA detected by supersensitive RT-PCR. Nevertheless, this would still
reflect disordered responses of LIFKO animals to inflammation. Levels
of cytokine expression in untreated and PBS-treated mice of both
genotypes are very low, at the limit of RT-PCR sensitivity. We
therefore chose to compare only induced levels of cytokine expression.
Overall, mRNA levels for pituitary cytokines were higher in animals
with LIF deficiency.
Higher levels of pituitary cytokines after LPS and TNF-
administration in the absence of LIF suggest that LIF is implicated in
the complex synergistic relations between circulating cytokines. Thus
an acute inflammatory response during endotoxemia is mediated by
induction of proinflammatory cytokines such as TNF-
(19, 28). Subsequently, TNF-
induces IL-1
(18),
which in turn, stimulates IL-6 synthesis and secretion
(17). LIF decreased serum TNF-
concentrations in vivo
(38) and in vitro (43). Such an
anti-inflammatory action of LIF is in accord with results demonstrating a protective effect of exogenous LIF in septic shock (40) and local inflammation (8). Absence of
LIF leads to TNF-
overproduction with subsequent increased IL-1
and IL-6 expression in LIFKO animals.
It is not clear whether LIF deficiency per se or lower corticosterone
levels result in higher cytokine production in knockout animals. High
levels of cytokines observed especially after 1-h treatment could be
responsible for the peak plasma ACTH (3, 37) noted in
LIFKO mice. We did not observe a corresponding corticosterone increase,
likely due to the experiment timing. Thus an absence of LIF, but not a
lower corticosterone, resulted in enhanced proinflammatory cytokine
production at the beginning of the inflammatory process. However, we
cannot exclude that lower plasma corticosterone responses in LIFKO mice
may contribute to later stimulation of IL-1 8 h after LPS treatment.
Increased pituitary cytokine induction may lead to pituitary SOCS-3 overexpression demonstrated in LIFKO animals. In these LIF-deficient animals, SOCS-3 was induced earlier, within 30 min, and remained elevated for up to 8 h after treatment. By inducing the JAK/STAT-3 pathway, proinflammatory cytokines stimulate both POMC and SOCS-3 transcription. SOCS-3, acting via an intracellular autocrine loop, negatively regulates cytokine signaling (4, 5) by inhibiting JAK kinase activity (10, 27). At the same time, SOCS-3 attenuates stimulatory effects of cytokines on pituitary POMC (5). These observations suggest that cytokine-induced SOCS-3 may mediate a pituitary response to inflammation. To test this hypothesis, we employed mouse pituitary corticotroph AtT20 cells treated with IL-6 that timely stimulates both SOCS-3 and POMC expression. In control cells treated with MM oligonucleotides, SOCS-3 expression induced by IL-6 was high when POMC expression was low. Treatment cells with SOCS-3 AS oligonucleotides resulted in a decrease of IL-6-induced SOCS-3 expression, whereas expression of POMC became induced. Statistical analysis shows a negative relationship between SOCS-3 and POMC gene expression. The results support the involvement of SOCS in regulation of the HPA axis. In the course of septic shock, a number of cytokines acting in synergy potentiate pituitary ACTH (22). The presence of rapid cytokine-inducible mechanisms restricting POMC overexpression could be an important step in preserving homeostasis. We earlier demonstrated attenuated POMC gene expression and ACTH secretion in LIFKO mice (1, 6, 14, 15). Simultaneously, SOCS-3 overexpression in response to LPS in LIFKO mice impacts on HPA axis functioning. Thus LIF deficiency may account for two different mechanisms leading to lowered HPA axis inflammatory responses.
Lower circulating ACTH and glucocorticoid levels, excessive production of pituitary cytokines, and SOCS-3 overexpression, which may reinforce suppression of the HPA inflammatory response, leads to increased inflammatory activity in LIFKO mice. This is reflected by accelerated ESR and increased SAA levels in these animals. SAA, an important acute-phase protein, is a sensitive indicator of inflammation (24), simultaneously providing enhanced protection from microorganisms (36). gp130 Cytokines induce SAA in an overlapping or redundant fashion when administered alone or in combination with IL-1. (36). The high levels of SAA observed in LIFKO mice could result from a strong inflammatory reaction occurring in the absence of LIF. Interestingly, even in untreated LIFKO animals, baseline SAA levels tend to be higher than in WT mice. This could reflect a compensatory elevation of other proinflammatory cytokines.
In summary, we demonstrate that pituitary LIF suppresses pituitary
cytokine levels and activates the ACTH responses to acute inflammation.
The negative correlation between pituitary SOCS and POMC expression
could result in lowering of HPA function and further propagation of the
inflammatory process. Figure 8 depicts complex relationships between LIF, other proinflammatory cytokines, and
SOCS-3 in the pituitary. The multifaceted cascade of cellular and molecular events required for systemic homeostasis in response to
infection or inflammation thus invoke both LIF and SOCS-3 in the
neuroimmunoendocrine interface.
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ACKNOWLEDGEMENTS |
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This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-54862 (V. Chesnokova) and DK-501238 (S. Melmed) and the Doris Factor Molecular Endocrinology Laboratory.
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FOOTNOTES |
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Address for reprint requests and other correspondence: V. Chesnokova, Dept. of Medicine, Division of Endocrinology, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048 (E-mail: chesnokovav{at}cshs.org).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published January 22, 2002;10.1152/ajpendo.00442.2001
Received 4 October 2001; accepted in final form 11 January 2002.
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