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Division of Endocrinology and Metabolism, Cedars-Sinai Research Institute, University of California School of Medicine, Los Angeles, California 90048
Address all correspondence and requests for reprints to: Shlomo Melmed, M.D., Division of Endocrinology and Metabolism, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, B-131, Los Angeles, California 90048. E-mail: melmed{at}cshs.org
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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), and IL-6 are the
most thoroughly characterized cytokines that function as bidirectional
regulators of these neuroendocrine-immune communications (5).
Recently, attention has been drawn to leukemia inhibitory factor (LIF),
a pleiotropic cytokine that belongs to a common cytokine family,
together with oncostatin M, IL-6, IL-11, ciliary neurotropic factor,
and cardiotropin-1 (6, 7, 8). LIF has diverse biological activities,
including a differentiation-inducing effect on myeloid leukemia cells,
regulation of hemopoietic cell proliferation and differentiation, bone
resorption, stimulation of neuronal growth and development, and
inhibition of totipotent mouse embryonic stem cell differentiation
without affecting proliferation (9). LIF is induced locally in a
variety of inflammatory conditions, is produced by immune cell lines,
and is required for neuronal response to injury (10, 11). LIF was shown
to be secreted by bovine pituitary follicular cells (12). In our laboratory, LIF expression has been demonstrated in murine corticotrophs and human fetal (13) and adult pituitary tissue (14). LIF stimulated POMC gene expression (14) and strongly potentiated CRH induction of POMC gene transcription and expression (15). In transgenic mice expressing pituitary-directed LIF driven by the rat GH promoter, LIF overexpression resulted in pituitary corticotroph hyperplasia (16). Delivery of LIF via osmotic pump implantation increased plasma ACTH and corticosterone levels in LIF knockout mice (17). LIF and LIF receptors were constitutively expressed in the normal mouse hypothalamus and pituitary and were induced (up to 6- and 4-fold, respectively) in vivo in response to lipopolysaccharide endotoxin (LPS). Furthermore, the LIF induction precedes increased peripheral ACTH stimulation caused by LPS (18). As we demonstrated recently, LIF modulates IL-1ß-induced activation of the hypothalamo-pituitary-adrenal (HPA) axis in mice (19).
Taken together, these data indicate that LIF is an inducible proinflammatory hypothalamo-pituitary cytokine that may function as either an autocrine or paracrine regulator of ACTH. Therefore, we sought to determine whether LIF is involved in the stress reaction of the HPA axis in vivo. In this study we employed LIF knockout (LIFKO) mice and show that in the absence of LIF, animals cannot maintain an appropriate stress-induced HPA axis activation. This defect is associated with deficient pituitary POMC gene expression in LIFKO animals. In contrast, injection of exogenous murine LIF to these LIF-depleted animals markedly increased pituitary POMC gene expression. LIF thus controls the development and functioning of the HPA axis.
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Materials and Methods |
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PCR DNA analysis
Sequences of primers and conditions for PCR analysis were
provided by Drs. Reto Gadient and Lisa Banner (Caltech, Pasadena, CA).
For mouse LIF expression detection, the sense primer sequence is
5'-CGCCTAACAT GACAGACTTC CCAT-3', and the antisense primer is
5'-AGGCCCCTCA TGACGTCTAT AGTA-3'. For LIFKO (neo) expression
detection, the sense primer is 5'-CCAGCTCTTC AGCAATATCA CGGG-3', and
the antisense primer is 5'-CCTGTCCGGT GCCCTGAATG AACT-3'. The PCR
reaction was performed under the following conditions: 1 x PCR
buffer, 2.5 mM MgCl2, 0.4 pmol/µl of each
primer, 0.1 mM deoxy-NTPs, 0.1 U/µl Taq
polymerase, and 50–100 ng genomic DNA for a total reaction volume of
50 µl. PCR was performed for 38 amplification cycles (95 C for 30
sec, 68 C for 45 sec, 72 C for 45 sec) with 3-min extinction at 72 C.
PCR was carried out using GeneAmp PCR system 9600 (Perkin-Elmer,
Norwalk, CT).
Tail biopsy, blood collection, and hormone assay
Five millimeters of mouse tail were cut under light isoflurane
narcosis (Isofluran, Abbott Laboratories, North Chicago, IL), and DNA
was extracted using the genomic DNA extraction system, Purigene
(Gentra, Research Triangle Park, NC). Whole blood was obtained either
immediately after decapitation or from the retroorbital sinus under
isoflurane narcosis using heparinized capillary tubes (Baxter, McGaw
Park, IL). Plasma was collected between 1000–1200 h in ice-chilled
tubes containing 0.1% EDTA, separated, and stored at -70 C until
assayed. Plasma ACTH was assayed using the ACTH double antibody kit
(Diagnostic Products Corp., Los Angeles, CA). Plasma corticosterone was
measured by RIA (ICN Biomedicals, Costa Mesa, CA). The sensitivities of
the ACTH and corticosterone assays were 10 pg/ml and 25 ng/ml,
respectively. Inter- and intraassay variabilities for ACTH were 8.9%
and 6.4%, respectively; inter- and intraassay variabilities for
corticosterone was 4.4% and 6.5%, respectively.
Injection of mycobacteria adjuvant
Experimental animals were administrated an intradermal tail base
injection of a 0.2-ml suspension (10 mg/ml) of ground, heat-killed
mycobacterium butiricum (Difco, Detroit, MI) in heavy paraffin oil
(Fluka Chemika-Biocemika, Buchs, Switzerland). At different time points
after injection (7, 10, and 14 days), blood was collected from the
retroorbital sinus, and plasma was stored at -20 C for hormone
measurements.
LIF injection
Murine LIF (12 µg) in sterile PBS, provided by Dr. R. Klupacs
(AMRAD, Victoria, Australia), was injected ip in 0.2 ml. Control
animals received 0.2 ml PBS, and all animals were killed 1 and 3 h
after injection.
Stress procedures
Restraint. Animals were restrained for 30 min in acrylic
cages, specifically designed for murine restraint (Fisher Scientific,
Pittsburgh, PA).
Immobilization. Mice were immobilized in a prone position on a board by taping limbs to a platform with their dorsal surface up and fixing their heads in a loop for 15 and 45 min. Animals were then immediately killed.
Tissue dissection and RNA isolation
Mice were decapitated, pituitary and hypothalamus were
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 (Life Technologies, Gaithersburg, MD) according to the
manufacturer’s instructions, in which 5–100 mg frozen tissue were
immersed in 1 ml Trizol solution and homogenized with a Polytron
homogenizer (Brinkmann Instruments, Westbury, NY). After final
dissolution in diethylpyrocarbonate-treated water, the RNA
concentration was spectrometrically quantitated, and RNA quality was
checked by gel electrophoresis.
Northern analysis
Northern analysis was performed using 2–10 µg total RNA/lane.
Samples were electrophoresed through a 1% agarose gel containing 2.2
M formaldehyde and transferred to a nylon membrane (Nytran
228, Schleicher and Schuell, Keene, NH), membranes were UV
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 were hybridized overnight at 65 C. Membranes were
then washed in 2 x SSC-0.1% SDS for 30 min, 1 x SSC-0.05%
SDS for 30 min, 0.5 x SSC-0.025% SDS for 1 h, and 0.1
x SSC-0.005% SDS for 1 h at 65 C, and filters were exposed to
Kodak Biomax film (Eastman Kodak, Rochester, NY) for 1–24 h for POMC,
cyclophilin, and ß-actin or for 72–96 h for CRH at -70 C.
Plasmids and templates
Mouse cyclophilin (mouse DECAprobe template) is a 721-bp
fragment of the mouse cyclophilin A gene. Mouse ß-actin (mouse
DECAprobe template) is a 1.076-kilobase fragment of the mouse
cytoplasmic ß actin gene. Both templates were purchased from Ambion
(Austin, TX). Murine POMC complementary DNA, 0.6-kilobase fragment,
encoding the 3' half of exon 3 was provided by Dr. Malcolm J. Low
(Portland, OR). Mouse CRH (pGEM vector containing 578 bp of exon II
from the CRH gene) was a gift from Dr. Audrey Seasholtz (Ann Arbor,
MI). Probes were labeled by random priming with the RadPrime DNA
Labeling System (Life Technologies).
Statistical analysis
Results are presented as the mean ± SEM and
were analyzed by Student’s t test. P <
0.05 was considered statistically significant.\.
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Results |
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).
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).
Effect of 45-min immobilization stress in LIFKO male mice
Basal plasma ACTH levels were similar in all three groups of
experimental animals. After 45 min of immobilization,
LIF+/+ and LIF+/- animals exhibited increased
plasma ACTH levels (from 34 ± 9 to 79 ± 19 pg/ml and from
49 ± 9 to 90 ± 11 pg/ml, respectively; P <
0.05 in both). In contrast, no increase in the stress level of ACTH was
observed in LIF-/- animals (42 ± 9 vs.
49 ± 6 pg/ml; Fig. 2A).
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).
Effect of 15- and 45-min immobilization stress on male
LIF+/+ and LIF-/-mice
After 15 min of immobilization, plasma ACTH levels rose in both
LIF+/+ (from 34 ± 9 to 365 ± 68 pg/ml;
P < 0.01) and LIF-/- animals
(from 49 ± 9 to 225 ± 66 pg/ml; P < 0.01).
However, animals harboring a disrupted LIF gene demonstrated attenuated
ACTH levels compared with those in wt mice (P < 0.05).
After 45 min of immobilization, plasma ACTH remained significantly
higher than the basal level (145 ± 23.6 vs. 34.17
± 8.63 pg/ml; P < 0.05) in
LIF+/+ mice, whereas in the
LIF-/- group of animals no elevation of plasma
ACTH (49 ± 9.3 and 51 ± 12.4 pg/ml, respectively) was
observed (Fig. 3A).
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).
Effect of mycobacterium adjuvant injection in female LIFKO mice
Seven days after the injection of adjuvant, plasma corticosterone
levels were increased in wt animals, whereas 10 or 14 days after
injection, corticosterone levels had returned to basal levels,
indicating transient adjuvant-induced activation of the HPA axis. No
activation of the HPA axis was noted in LIFKO animals throughout the
observation period. By 7 days after injection, wt animals demonstrated
doubling of plasma corticosterone levels compared to levels in animals
harboring the disrupted LIF gene (153 ± 22 vs. 78
± 15 ng/ml; P < 0.05; Fig. 4).
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). In
contrast, levels of pituitary POMC mRNA in mice harboring a disrupted
LIF gene was very low. LIF+/- mice showed
intermediate levels of pituitary POMC mRNA, whereas in
LIF+/+ animals, levels of POMC mRNA were highest
(Fig. 5B). After 15 min of immobilization, pituitary POMC mRNA levels
increased in all three groups of experimental animals. However, this
increase was lowest in LIF-/- mice,
intermediate in LIF+/- mice, and highest in
LIF+/+ animals. Similar changes in POMC mRNA
levels were observed 45 min after immobilization (Fig. 5C).
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).
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). Plasma
corticosterone was increased 4-fold compared with that in control
animals injected with PBS (376 ± 70 vs. 79 ± 18
ng/ml; P < 0.01) 1 h after LIF injection. Three
hours after injection, the plasma corticosterone level in LIF-injected
animals were still much higher than the control value (259 ± 28
vs. 58 ± 13 ng/ml; P < 0.05).
In LIFKO mice, levels of pituitary POMC mRNA were markedly increased
3 h after LIF injection compared with those in animals injected
with PBS alone (Fig. 7A).
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). Three
hours after injection, POMC mRNA levels increased in LIF-treated normal
animals (Fig. 7C). |
Discussion |
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Strikingly, mice with LIF deficiency do not respond to 30 and 45 min of psychological stress with elevation of blood ACTH, whereas their corticosterone stress response appeared intact. These results imply that stressed LIFKO animals can maintain increased levels of plasma corticosterone without increasing circulating ACTH levels. Plasma ACTH, after peaking at 30 min of immobilization, progressively declines because of glucocorticoid negative feedback effects (21, 22). To investigate the overall capability of knockout mice to increase their levels of plasma ACTH, we tested short term (15-min) immobilization and compared knockout animals with normal wt littermates. Although LIFKO animals are able to mount a plasma ACTH response to acute 15-min stress, this elevation is much lower than that in wt animals. This increase in ACTH is dissipated 45 min after the beginning of the stress, whereas in LIF+/+ mice ACTH remains persistently high. Thus, mice bearing a disrupted LIF gene mount a deficient ACTH stress response. The decreased ACTH still appears sufficient to allow a normal corticosterone stress response in LIFKO mice. However, the observed elevation of corticosterone levels in these animals may be mediated by extrapituitary mechanisms, including sympathetic nerves that activate the adrenal cortex via release of catecholamines (23). Furthermore, psychological stress elevates plasma levels of IL-6, which is known to be a direct stimulator of adrenal steroidogenesis (24). Although LIFKO mice demonstrate normal acute corticosterone stress responses, alterations in hypothalamic-pituitary function may diminish the ability of these animals to endure chronic stressful conditions.
Infection and inflammation are potent stimulators of the HPA axis (2, 25), and injection of mycobacterial Freund’s adjuvant into rats elicits inflammatory joint disease and causes transient activation of the HPA axis (26). In mice, the HPA axis is also activated for 7–14 days after injection. As the severity and duration of the inflammatory process are enhanced by female sex hormones (27), we used female mice for the experiment. We did not observe activation of the HPA axis in LIF-/- animals, whereas their heterozygous littermates demonstrated a significant increase in plasma corticosterone 7 days after adjuvant injection. These results show that during chronic stress, LIFKO animals cannot maintain an appropriate level of HPA axis activation. It has been suggested that the rise in circulating adrenocortical steroids during inflammation might be necessary to terminate activated defense mechanisms and return the organism to homeostasis (28). In the absence of this feedback mechanism, the magnitude and duration of inflammation are increased (29, 30, 31). The inability of LIF-deficient animals to respond to inflammatory stimuli with HPA axis activation implicates LIF in the HPA response during inflammatory stress, and the absence of this cytokine may lead to impaired physiological communication between the immune and endocrine systems. These findings are in agreement with our observation that activation of the HPA axis in response to ip injection of proinflammatory cytokine IL-1ß in LIFKO mice is significantly lower than that in their wt littermates (19).
Low ACTH responses to acute psychological or low corticosterone responses to chronic inflammatory stress in animals with LIF deficiency may be a result of altered development of the HPA axis during ontogenesis. We found that although hypothalamic CRH mRNA levels in LIFKO mice were elevated, levels of pituitary POMC mRNA were very low compared with those in the other experimental groups. Thus, increased hypothalamic CRH synthesis may play a compensatory role to sustain a sufficient level of pituitary POMC in LIF-deficient animals. We also showed a significant increase of pituitary POMC mRNA in normal and heterozygous animals in response to immobilization stress. These results are in agreement with previous data in which an increase in the transcriptional rate of the POMC gene has been shown to occur within 30 min after CRH stimulation (32, 33) and 30–120 min after insulin-induced hypoglycemia (34). In LIF-deficient animals, the rise in POMC mRNA levels in response to stress was more modest than that in control groups in both experiments. It appears, therefore, that mechanisms underlying the depletion of ACTH result in decreased pituitary POMC expression in LIFKO animals. Previous in vitro studies in our laboratory have clearly shown that LIF increases basal and CRH-induced POMC mRNA gene transcription (4), and LIF and CRH share similar binding elements on the rat POMC gene promoter (15). Moreover, LIF modulates early embryonic determination of specific human pituitary cells, producing ACTH (14, 16). In our present experiments, LIF is shown to exhibit an intrapituitary role as a paracrine or autocrine regulator of ACTH in vivo. We assume that a deficiency of pituitary LIF during development might lead to impaired POMC gene expression in the experimental LIFKO mice.
To confirm the role of LIF in activation of the HPA axis in vivo, we studied the effect of exogenous murine LIF on plasma corticosterone and ACTH levels and expression of the POMC gene in LIFKO and normal C57BL/6 mice. Injection of murine LIF leads to a marked increase in pituitary POMC mRNA and plasma ACTH and corticosterone levels. POMC gene expression in LIFKO animals is more sensitive to the effect of exogenous LIF, and POMC mRNA induction by LIF injection is more pronounced in knockout than in normal C57BL/6 animals, even considering that a double amount of total pituitary RNA was tested for LIFKO mice. Three hours after LIF injection, LIFKO mice still exhibit higher ACTH levels compared with wt controls, whereas normal animals do not differ from controls at this time point. This is probably due to changes in LIF receptor synthesis and turnover in the pituitary of LIF-deficient animals. It is known that LIF receptors are expressed in murine pituitary corticotrophs (13), and their expression is up-regulated by LPS treatment (18). Our results suggest that in the absence of LIF, animals develop increased LIF receptor sensitivity, allowing for the marked rise in levels of POMC mRNA in response to exogenous LIF. This observation further demonstrates that LIF stimulates the acute release of pituitary ACTH to the periphery and subsequently provokes activation of the pituitary POMC gene.
It is unclear whether LIF, a variably glycosylated protein
(38,000–67,000 kDa), comprised of approximately 180 amino acid
residues (35), can penetrate the blood-brain barrier. Although small
amounts of cytokines (IL-1, IL-2, and TNF) can reach the brain (36, 37), recent suggestions that cytokines may act as autocrine or
paracrine agents (4, 38) seem more reasonable.
The stress response of the HPA axis plays a crucial role in health,
because HPA hormones are involved in the regulation of homeostasis, the
immune system, and neuronal survival (3). From a large body of recent
data it appears that several chemical mediators play a key role in
coupling the neuroendocrine and immune systems. Concomitantly, recent
studies have shown that IL-1ß, TNF, and IL-6 are potent activators
of the HPA system, even though their cellular sites of action on the
neuroendocrine axis as well as their ability to cross the blood-brain
barrier are under debate (40). These effects of cytokines on HPA
function appear to be a crucial mechanism for the inflammatory
response. We have also shown that hypothalamic and pituitary LIF are
induced after LPS treatment in vivo (18). However, cytokine
action within the brain is not limited to inflammatory stimuli.
Microinjections of IL-1 into the anterior hypothalamus inhibit the
ACTH response to immobilization stress (39). Here we demonstrate that
LIF, a pleiotropic immune cytokine, regulates stress responses of the
HPA axis, maintains appropriate levels of ACTH, and presumably provides
continued activation of this system during stress and inflammatory
disease.
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Footnotes |
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Received November 20, 1997.
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