Leukemia inhibitory factor regulates glucocorticoid receptor expression in the hypothalamic-pituitary-adrenal axis
Anastasia Kariagina,
Svetlana Zonis,
Mahta Afkhami,
Dmitry Romanenko, and
Vera Chesnokova
Cedars-Sinai Medical Center and David Geffen School of Medicine at University of California, Los Angeles, California
Submitted 7 December 2004
; accepted in final form 20 June 2005
 |
ABSTRACT
|
---|
Leukemia inhibitory factor (LIF) is a pleiotropic cytokine belonging to the gp130 family. LIF is induced peripherally and within the brain during inflammatory or chronic autoimmune diseases and is a potent stimulator of the hypothalamic-pituitary-adrenal (HPA) axis. Here we investigated the role of LIF in mediating glucocorticoid receptor (GR) expression in the HPA axis. LIF treatment (3 µg/mouse, ip) markedly decreased GR mRNA levels in murine hypothalamus (5-fold, P < 0.01) and pituitary (1.7-fold, P < 0.01) and downregulated GR protein levels. LIF decreased GR expression in murine corticotroph cell line AtT20 within 2 h, and this effect was sustained for 8 h after treatment. LIF-induced GR mRNA reduction was abrogated in AtT20 cells overexpressing dominant-negative mutants of STAT3, indicating that intact JAK-STAT signaling is required to mediate LIF effects on GR expression. Conversely, mice with LIF deficiency exhibited increased GR mRNA levels in the hypothalamus and pituitary (3.5- and 3.5-fold, respectively; P < 0.01 for both) and increased GR protein expression when compared with wild-type littermates. The suppressive effects of dexamethasone on GR were more pronounced in LIF-null animals. These data suggest that LIF maintains the HPA axis activation by decreasing GR expression and raise the possibility that LIF might contribute to the development of central glucocorticoid resistance during inflammation.
LIF-null mice; AtT20 cells
GLUCOCORTICOIDS HAVE A WIDE RANGE of functions in regulating energy homeostasis, responses to stress, immune defenses, behavioral responses, and brain activity. Glucocorticoids also play a major role in negatively regulating the functioning of the hypothalamic-pituitary-adrenal (HPA) axis. Glucocorticoids signal by binding to two distinct cytosolic receptors, the mineralocorticoid receptor and the ubiquitous glucocorticoid receptor (GR) (3, 13, 29). GR-mediated signaling suppresses the HPA axis at multiple levels. In the pituitary, GR signaling inhibits expression of proopiomelanocortin (POMC) by directly binding to the glucocorticoid response element on the POMC promoter (27). However, most GR-mediated signaling indirectly regulates target genes by influencing intermediary transcription factors such as Jun-B, NF-
B, STAT3, and STAT5 (5, 12, 20, 39).
Glucocorticoids can suppress inflammation by inhibiting expression of proinflammatory cytokines through a number of mechanisms (3, 29). Conversely, inflammation is frequently accompanied by impaired central or local tissue-specific GR function (11, 22, 26, 36, 37). For example, attenuation of GR-mediated signaling occurs in peripheral lymphocytes in patients with asthma (21, 22) and rheumatoid arthritis (11). Proinflammatory cytokines such as tumor necrosis factor-
(TNF-
) and interleukin-1
(IL-1
) that are typically expressed in such conditions locally attenuate glucocorticoid effects in target tissues (17, 18, 26) by reducing the affinity of the GR for its ligand (14, 18), promoting expression of a dominant-negative GR
isoform (36), or interfering with GR shuttling from the cytoplasm to the nucleus (26).
Leukemia inhibitory factor (LIF) is a proinflammatory cytokine member of the gp130 family that is induced in many inflammatory diseases (8, 10). LIF binds to a heterodimeric complex that includes the specific LIF receptor (LIFR) and a promiscuous gp130 subunit that is shared among all members of the gp130 cytokine family. Upon ligand binding, the LIFR-gp130 complex can activate the JAK-STAT pathway, the MAPK pathway, or both, depending on the cell type (2). Previous studies from our laboratory (1) showed that LIF was a strong stimulator of the HPA axis. LIF potently induces POMC expression and ACTH secretion, and LIF-deficient animals exhibit a shortened ACTH response to psychological and inflammatory stress (810). Transgenic mice overexpressing pituitary LIF show not only elevated ACTH and corticosterone levels but also reduced sensitivity of pituitary POMC to the inhibitory action of dexamethasone (DEX) (38). These data suggest that LIF may attenuate negative feedback regulation of the HPA axis. The goal of the present study was to test this possibility.
Here, we report that LIF treatment reduced GR mRNA and protein expression in the HPA axis. In contrast, mice lacking LIF exhibited elevated GR mRNA and protein levels in the hypothalamus and pituitary. LIF caused a rapid decrease of GR expression in AtT20 murine corticotroph cells in a range of doses, and these effects were abrogated in AtT20 cells overexpressing dominant-negative forms of STAT3. Our data are most consistent with the interpretation that LIF is an essential mediator of HPA axis GR expression and may contribute to impaired negative feedback regulation of the HPA axis. Furthermore, although several signaling options are available to LIF, the effects of LIF on GR expression appear to be mediated predominantly or perhaps solely through the JAK-STAT signaling pathway.
 |
MATERIALS AND METHODS
|
---|
Experimental animals.
C57Bl/6J female mice were purchased from the Jackson Laboratory (Bar Harbor, ME). Lif/ mice, originally generated by Dr. Colin L. Stewart (Roche Institute of Molecular Biology, Roche Research Center, Nutley, NJ) on C57Bl/6J and DBA/2 heterozygous background, were back-crossed to C57BL/6J mice for at least five generations before being used in our experiments. LIF-null mice as well as wild-type littermates were obtained through breeding of heterozygous Lif+/ females and males. Genotype of pups was determined by PCR analysis of tail DNA (8). Five animals were housed per cage with free access to water and food at a standard 12:12-h dark-light cycle. The Institutional Animal Care and Use Committee at Cedars-Sinai approved all experimental procedures before we began our investigation.
In vivo treatments.
Mice were injected intraperitoneally with recombinant murine LIF (3 µg/mouse; Chemicon International, Temecula, CA) in 200 µl of normal saline. Control animals received saline only. All mice were killed 3 h after injection. DEX (Sigma) was dissolved in 100% ethanol, diluted to a final concentration of 5 mg in a 6% ethanol-normal saline solution, and injected intraperitoneally (total injected volume 200 µl). Control animals were injected with the same volume of 6% ethanol in normal saline. Three hours after treatment, mice were killed, and the hypothalamus, pituitary, and liver were dissected, snap-frozen in liquid nitrogen, and stored at 80°C until RNA or protein extraction.
Cell culture and treatments.
Murine corticotroph AtT20 cells (American Type Culture Collection, Rockville, MD) were grown in low-glucose-DMEM supplemented with 100 U/ml streptomycin, 100 U/ml penicillin, and 10% fetal calf serum (Mediatech, Herndon, VA). Before experimental treatments, cells were kept in serum-free medium for 18 h. Cells were treated with recombinant murine LIF (250 ng/ml), TNF-
(10 ng/ml), IL-1
(1 ng/ml), or IL-6 (10 ng/ml; all from R&D Systems, Minneapolis, MN). Two distinct types of dominant-negative STAT3 mutant constructs were used. The first (STATF) included a phenylalanine substitution at a tyrosine residue near the carboxyl-terminal residue (Tyr705). The second dominant-negative STAT3 construct (STATD) contained two alanine substitutions at positions important for STAT3 DNA binding (Glu434 and Glu435). These mutants were transfected into AtT20 cells, and transformants were selected with G418 (6).
Northern blot analysis.
Total RNA was extracted from tissues of AtT20 cells using TRIzol reagent (Invitrogen, Carlsbad, CA), according to the manufacturers protocol, and quantified spectrophotometrically. Total RNA (10 µg) was resolved on denaturing 1% agarose gel, transferred to a Hybond N+ membrane, and hybridized with a 32P-labeled fragment of murine GR (obtained by PCR, GenBank accession no. X04435) or 18S RNA (loading control; Decatemplate, Ambion, Austin, TX). Developed films were scanned, and densitometry was performed using Kodak imaging software.
Real-time PCR.
Total RNA (2.5 µg) were treated with deoxyribonuclease I (DNase I; Ambion, Austin, TX) and reverse transcribed using OmniScript reverse transcriptase (Qiagen, Valencia, CA). Real-time PCR reactions were performed using an iCycler thermal cycler with an optical module (Bio-Rad, Hercules, CA) and a fluorescent reporter dye (SYBR Green I; Molecular Probes, Eugene, OR) as described (19). Primers were as follows: 18S sense, 5'-aaacggctaccacatccaag-3'; antisense, 5'-cctccaatggatcctcgtta-3' (product size 155 bp, melting temperature Tm = 88°C); GR sense, 5'-ggaagttaatatttgccaatggac-3'; GR antisense, 5'-cgcagaaaccttgactgtagc-3' (product size 150 bp, Tm = 89°C). The relative quantity of each gene in experimental samples was determined from the corresponding standard curve and normalized to 18S. Levels of mRNA are presented as arbitrary units referenced to the wild-type control, which was assigned an arbitrary value of 1.0 for comparative purposes.
Western blot analysis.
Total protein as well as cytosolic and nuclear fractions were isolated from hypothalamus, pituitary, and AtT20 cells as previously described (30). Proteins were quantitated using a bicinchoninic acid protein assay kit (Pierce, Rockford, IL). Twenty micrograms per lane were resolved on 8% polyacrylamide gel (Express Gels; ISC BioExpress, Kaysville, UT) and transferred to an Immobilon membrane (Millipore, Bedford, MA). After blocking with 5% milk in a buffer, membranes were incubated with anti-GR antibody (1:5,000 dilution; Affinity Bioreagents, Golden, CO) and anti-
-actin antibody (1:2,000 dilution; Sigma, St. Louis, MO). After incubation with secondary antibodies (Amersham, Piscataway, NJ), membranes were treated with enhanced chemiluminescence (ECL) or ECL plus reagents (Amersham) and exposed on X-ray film. Developed films were scanned, and densitometry was performed using Kodak imaging software.
Statistical analysis.
Data were analyzed by ANOVA, followed by a nonparametric Mann-Whitney test or Students t-test. All data are presented as means ± SE.
 |
RESULTS
|
---|
LIF reduces GR expression in vivo.
To address the question of whether LIF contributes to negative feedback regulation of the HPA axis, wild-type mice were injected with recombinant murine LIF, and GR protein and mRNA levels were analyzed in the hypothalamus and pituitary. Three hours after LIF treatment, GR protein levels in whole cell lysate, cytoplasmic fractions, and nuclear fractions were all decreased in the hypothalamus (Fig. 1, A and C). In the pituitary the diminished GR protein levels were even more evident (Fig. 1, B and D). We also observed a reduction in GR mRNA levels in the hypothalamus and pituitary (P < 0.01 for both) compared with control mice injected with saline (Fig. 1, E and F).

View larger version (30K):
[in this window]
[in a new window]
|
Fig. 1. Effects of LIF injection on glucocorticoid receptor (GR) and protein mRNA levels in wild-type mice. Animals were killed 3 h after treatment. Western blot analysis of GR in whole cell lysate (A and B) cytosolic (cyto) and nuclear (nucl) fractions in hypothalamus (C) and pituitary (D), and real-time PCR measurements of hypothalamic (E) and pituitary (F) GR mRNA levels. Results are expressed in arbitrary units. Cont, PBS injection. Values are means ± SE of 3 replicate measurements. Data are representative of 3 experiments; n = 810 animals/group. **P < 0.01 compared with control.
|
|
LIF downregulates GR expression in vitro.
We previously reported that LIF strongly increased plasma corticosterone levels in vivo (8). It is possible that the reduction in GR mRNA expression in the hypothalamus and pituitary that we observed might have been secondary to increased plasma levels of corticosterone. To evaluate this possibility, we treated mouse AtT20 pituitary corticotrophs with LIF (250 ng/ml) for 4 h. LIF in a range of doses diminished GR expression (Fig. 2A). Treatment with LIF (10 ng/ml) reduced GR mRNA levels in AtT20 cells beginning after 2 h of treatment, was sustained for
8 h, and by 24 h GR expression had returned to baseline levels (Fig. 2B).

View larger version (35K):
[in this window]
[in a new window]
|
Fig. 2. Effects of LIF on GR mRNA levels in AtT20 cells. A: cells were treated with different doses of LIF and harvested 4 h later. Experiment was performed twice with similar results, and a representative blot is shown. B: cells were treated with LIF (10 ng/ml) and harvested at indicated time points. A representative blot is shown. Relative abundance of GR mRNA was quantified by densitometry and normalized against levels of 18S mRNA in each sample. Optical density was standardized in relation to control values (taken as 1) and shown as fold increase. Bars show means ± SE of 3 independent Northern blots. **P < 0.01 compared with control. Cells were treated with 10 ng/ml TNF- (C) or IL-6 (D) and harvested at indicated time points. Experiment was performed twice with similar results.
|
|
To address the question of specificity of LIF action, we treated AtT20 cells with recombinant murine TNF-
, IL-1
, or IL-6 (another gp130 cytokine). None of these cytokines altered GR mRNA expression 224 h after treatment (Fig. 2, C and D, and data not shown). These results support the interpretation that LIF specifically and directly reduces GR mRNA expression and that this decrease may not be mediated by glucocorticoids.
To determine whether the LIF-induced decrease in GR mRNA levels was associated with a parallel decrease in GR protein levels, we performed Western blotting of whole cell lysates and cytoplasmic and nuclear fractions of AtT20 cells treated with 10 ng/ml LIF. No changes in GR protein levels were noted in whole cell lysates during the course of the experiment (Fig. 3A). The relative abundance of GR in cytosolic and nuclear fractions was quantified by densitometry and normalized against levels of
-actin in each sample. LIF treatment for 2 h markedly decreased cytosolic GR protein levels (P < 0.05, Fig. 3B), whereas the nuclear fraction of GR protein was increased (P < 0.05, Fig. 3C), consistent with the interpretation that LIF induces GR translocation from the cytoplasm to the nucleus. The results show that by 8 h after treatment, GR protein levels returned to baseline in both cytoplasm and nucleus (Fig. 3, D and E). Decreased cytoplasmic GR expression 24 h after treatment (P < 0.05 compared with control) can be attributed to the delayed effects of GR mRNA decline in LIF-treated cells (Fig. 2). These results suggest that LIF might be also involved in regulating nuclear-cytoplasmic shuttling of GR.

View larger version (33K):
[in this window]
[in a new window]
|
Fig. 3. Effects of LIF on GR protein levels in AtT20 cells. Western blot analysis of GR protein levels in whole cell lysate (A), cytosolic (B), and nuclear fractions (C) of AtT20 cells treated with LIF (10 ng/ml) and harvested at indicated time points. Relative abundance of GR in cytosolic (D) and nuclear fractions (E) was quantified by densitometry and normalized against levels of -actin in each sample. Optical density was standardized in relation to the control values (taken as 1) and shown as fold increase. Bars show means ± SE of 3 independent Western blots. *P < 0.05 compared with control. C, untreated cells.
|
|
LIF effects on GR expression are mediated by the JAK-STAT signaling pathway.
In mouse corticotrophs, LIF signaling utilizes the JAK-STAT3 signaling cascade (6). JAK-STAT signaling in AtT20 cells was inhibited by stably transfecting wild-type STAT3 (STATW, control) or a dominant-negative STAT3 with a mutation on either the phosphorylation site (STATF) or the DNA-binding domain (STATD) (6). After treatment of stably transfected AtT20 cells with LIF, Northern blot analysis showed decreased GR mRNA levels in cells expressing STATW as expected. In contrast, LIF treatment of cells that overexpressed either of the dominant-negative constructs failed to reduce GR mRNA expression (Fig. 4). These results indicate that LIF treatment directly inhibits GR expression via JAK-STAT pathway stimulation, and thus provide support for the interpretation that LIF regulates GR expression by a mechanism that depends upon intact JAK-STAT signaling.

View larger version (45K):
[in this window]
[in a new window]
|
Fig. 4. Effects of LIF on GR expression in dominant-negative STAT3 mutant cells. A: Northern blot analysis of GR mRNA in regular AtT20 cells and AtT20 cells overexpressing dominant-negative STAT3 and treated with LIF (10 ng/ml). STATW, cells overexpressing wild-type STAT3; STATD, cells overexpressing STAT3 mutated on DNA binding site; STATF, cells overexpressing STAT3 mutated on phosphorylation site; unt, untreated. A representative blot is shown. B: relative abundance of GR mRNA was quantified by densitometry and normalized against levels of 18S mRNA in each sample. Optical density was standardized in relation to the control values (taken as 1) and shown as fold increase. Bars show means ± SE of 3 independent Northern blots. *P < 0.05 compared with untreated AtT20 cells. P < 0.05 compared with untreated cells overexpressing STATW.
|
|
GR levels in LIF-null mice.
To determine the physiological role of LIF in regulating GR in the HPA axis, we examined expression of GR in Lif/ mice. Compared with wild-type mice, GR mRNA levels were elevated in the hypothalamus (3.6-fold, P < 0.01) and pituitary (3.6-fold, P < 0.01) but not in the liver of Lif/ mice (Fig. 5A). Whole cell GR protein levels were also increased in both the hypothalamus and pituitary of Lif/ animals relative to wild-type littermates (Fig. 5, B and C). These findings demonstrate that genetic deficiency of LIF results in augmented GR mRNA and protein levels in the HPA axis, and thus support the in vivo relevance of results obtained from our cell culture studies.

View larger version (24K):
[in this window]
[in a new window]
|
Fig. 5. GR mRNA and protein levels in Lif/ mice. A: GR mRNA levels are expressed in arbitrary units after real-time PCR. Values are means ± SE of 3 replicate measurements. Data are representative of 2 experiments; n = 810 animals/group. **P < 0.01 compared with wild-type; Western blot analysis of GR protein levels in whole cell lysate of hypothalamus (B) and pituitary (C); n = 35 mice/group.
|
|
GR mRNA autoregulation in Lif/ mice.
To explore whether LIF was involved in GR autoregulation, we treated LIF-null and wild-type mice with DEX, killed them 2 h later, and determined GR mRNA levels in the hypothalamus, pituitary, and liver. DEX suppression of hypothalamic GR mRNA levels was more pronounced in Lif/ than in wild-type mice (94% inhibition in Lif/ mice vs. 75% in wild-type animals, P < 0.01). Similarly, in the pituitary, DEX lowered GR mRNA expression (89% inhibition in LIF-deficient mice and only 46% inhibition in wild-type animals, P < 0.01). Thus the HPA axis in Lif/ animals appeared to be more sensitive to the suppressive action of DEX. At the same time, mouse genotype (LIF-null vs. wild-type) did not affect the magnitude of DEX-induced GR inhibition in the liver (Fig. 6).

View larger version (12K):
[in this window]
[in a new window]
|
Fig. 6. Effects of dexamethasone (DEX) on GR mRNA levels in wild-type and Lif/ mice. Animals were killed 2 h after ip treatment with 5 mg/mouse DEX. Results are presented as %inhibition relative to mice treated with vehicle alone (=100%). All values represent means ± SE of 3 replicate measurements. Experiment was performed twice with similar results; n = 810 animals/group. **P < 0.01 compared with wild-type.
|
|
 |
DISCUSSION
|
---|
Impaired GR sensitivity to corticosteroids during stress and inflammation may be attributed to multiple and diverse mechanisms, but the details are not fully understood on a molecular level. LIF is expressed in the hippocampus, hypothalamus, and pituitary (8, 10, 33) and is markedly elevated in response to acute and chronic inflammation (7, 9) and injury (4). Furthermore, plasma LIF levels correlate with the disease severity (34). LIF stimulates the HPA axis (1) and induces POMC expression and ACTH secretion, and LIF-deficient animals exhibit a shortened ACTH response to stress (810). Transgenic mice overexpressing pituitary LIF exhibit elevated ACTH and corticosterone levels and reduced sensitivity of pituitary POMC to DEX inhibition (38).
Here, we show that LIF attenuates the HPA axis negative feedback response by inhibiting GR expression. Treatment of wild-type mice with LIF reduces GR protein levels in the hypothalamus and pituitary, in whole cell lysates, and in both cytoplasmic and nuclear fractions. Hypothalamic and pituitary GR mRNA expression was also decreased 3 h after LIF injection. Accordingly, Lif/ mice manifested increased levels of GR mRNA and protein in the hypothalamus and pituitary. Experiments in vitro confirmed a direct negative effect of LIF on GR expression. In mouse corticotrophs, GR mRNA levels were decreased for 28 h after LIF treatment and returned to baseline by 24 h. Inhibition of GR expression by LIF was mediated by signaling, utilizing the JAK-STAT pathway, specifically STAT3.
Recent studies have revealed that proinflammatory cytokines can influence the expression and function of GR. For example, treatment with cytokines or a cytokine inducer (LPS) alter GR expression in a number of cells and tissues, including T cells (18), monocyte/macrophages (14, 15), lung (31), and liver (16). However, in our experiments, the proinflammatory cytokine IL-6 (which belongs to the same gp130 cytokine family as LIF) did not change GR expression in AtT20 cells. Also, in contrast with a previous report that TNF-
and IL-1
could induce the GR
isoform and negatively regulate GR function in human fibroblasts (36), our data showed that TNF-
or IL-1
treatment did not affect GR expression in AtT20 cells, perhaps because of the absence of the GR
isoform in mouse corticotrophs (25). The explanation for these discrepancies is uncertain, but it should be noted that regulation of GR transcription appears to be under the control of several tissue-specific promoters (23). Hence, it is possible that different cytokines may have tissue-specific effects on GR expression and function.
Our data show that, in vitro, LIF alters subcellular localization but not overall cellular levels of GR. GR exists primarily in the cytoplasm but can translocate to the nucleus upon activation, where it binds to hormone response elements or interacts with various transcription factors. The amount of GR protein in the cytosolic fraction of AtT20 cells paralleled the decline in GR mRNA that occurred 2 h after LIF treatment, yet simultaneously, nuclear GR protein levels were increased. LIF-induced GR nuclear translocation decreases GR mRNA levels. Thus the GR receptor can recognize a specific binding sequence within the receptor cDNA and downregulate its own expression (35). The decreased cytoplasmic GR protein levels observed in AtT20 cells 24 h after treatment probably resulted from a preceding decrease in GR gene transcription. Therefore, it seems likely that GR protein levels may decline at a later time after LIF treatment.
LIF treatment markedly reduced GR mRNA levels both in vivo and in vitro. However, whereas in vivo GR protein levels decreased, in vitro LIF caused redistribution of GR from the cytoplasm to the nucleus. These discrepancies can be explained by the effects of high plasma levels of corticosterone observed in mice after LIF injection (8, 10). In addition to LIF effects, induced corticosterone levels can not only further diminish GR gene transcription (28) but also decrease the receptor half-life (24) by ubiquitin-dependent proteosomal degradation (32) in both the hypothalamus and the pituitary.
Consistent with the results obtained after LIF treatment, Lif/ animals demonstrated markedly increased GR mRNA and protein levels in the hypothalamus and pituitary relative to wild-type littermates. Thus, whereas LIF treatment in vitro resulted in a redistribution of GR, genetically induced LIF deficiency led to constitutively increased cellular GR protein levels as a consequence of induced GR mRNA expression in LIF-deficient animals. Importantly, the difference in GR expression between LIF-null and wild-type mice appears to be attributed to the HPA axis, since there was no difference in liver GR mRNA levels between LIF-null and wild-type mice.
Taken together, our studies demonstrate that LIF negatively regulates GR expression in the HPA axis under basal conditions. These data also suggest that LIF not only stimulates acute pituitary POMC induction and ACTH release (810) but that by suppressing GR expression LIF may also promote sustained HPA axis activation. Short-term inhibition of GR expression observed in pituitary cells may prolong the ACTH response to inflammatory stimuli and thus limit immune activation. Although our study did not involve experimental models of inflammatory diseases, our results suggest that LIF may contribute to the development of short-term central glucocorticoid resistance during inflammation by suppressing GR expression in the HPA axis. An important goal of future studies will be to directly test this hypothesis in appropriate animal models of inflammatory disease, and our data here now provide a conceptual foundation to pursue such studies.
 |
GRANTS
|
---|
This work was supported by a grant (DK-54862 to V.Chesnokova) from the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
 |
ACKNOWLEDGMENTS
|
---|
We thank Zanna Felsher for technical assistance.
 |
FOOTNOTES
|
---|
Address for reprint requests and other correspondence: V. Chesnokova, Dept. of Medicine, Div. of Endocrinology, Davis Bldg., Rm. 3019, 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.
 |
REFERENCES
|
---|
- Akita S, Webster J, Ren SG, Takino H, Said J, Zand O, and Melmed S. Human and murine pituitary expression of leukemia inhibitory factor. Novel intrapituitary regulation of adrenocorticotropin hormone synthesis and secretion. J Clin Invest 95: 12881298, 1995.[ISI][Medline]
- Auernhammer CJ and Melmed S. Leukemia-inhibitory factor-neuroimmune modulator of endocrine function. Endocr Rev 21: 313345, 2000.[Abstract/Free Full Text]
- Bamberger CM, Schulte HM, and Chrousos GP. Molecular determinants of glucocorticoid receptor function and tissue sensitivity to glucocorticoids. Endocr Rev 17: 245261, 1996.[Abstract]
- Banner LR and Patterson PH. Major changes in the expression of the mRNAs for cholinergic differentiation factor/leukemia inhibitory factor and its receptor after injury to adult peripheral nerves and ganglia. Proc Natl Acad Sci USA 91: 71097113, 1994.[Abstract/Free Full Text]
- Biola A, Lefebvre P, Perrin-Wolff M, Sturm M, Bertoglio J, and Pallardy M. Interleukin-2 inhibits glucocorticoid receptor transcriptional activity through a mechanism involving STAT5 (signal transducer and activator of transcription 5) but not AP-1. Mol Endocrinol 15: 10621076, 2001.[Abstract/Free Full Text]
- Bousquet C and Melmed S. Critical role for STAT3 in murine pituitary adrenocorticotropin hormone leukemia inhibitory factor signaling. J Biol Chem 274: 1072310730, 1999.[Abstract/Free Full Text]
- Butzkueven H, Zhang JG, Soilu-Hanninen M, Hochrein H, Chionh F, Shipham KA, Emery B, Turnley AM, Petratos S, Ernst M, Bartlett PF, and Kilpatrick TJ. LIF receptor signaling limits immune-mediated demyelination by enhancing oligodendrocyte survival. Nat Med 8: 613619, 2002.[CrossRef][ISI][Medline]
- Chesnokova V, Auernhammer CJ, and Melmed S. Murine leukemia inhibitory factor gene disruption attenuates the hypothalamo-pituitary-adrenal axis stress response. Endocrinology 139: 22092216, 1998.[Abstract/Free Full Text]
- Chesnokova V, Kariagina A, and Melmed S. Opposing effects of pituitary leukemia inhibitory factor and SOCS-3 on the ACTH axis response to inflammation. Am J Physiol Endocrinol Metab 282: E1110E1118, 2002.[Abstract/Free Full Text]
- Chesnokova V and Melmed S. Leukemia inhibitory factor mediates the hypothalamic pituitary adrenal axis response to inflammation. Endocrinology 141: 40324040, 2000.[Abstract/Free Full Text]
- Chikanza IC. Mechanisms of corticosteroid resistance in rheumatoid arthritis: a putative role for the corticosteroid receptor beta isoform. Ann NY Acad Sci 966: 3948, 2002.[Abstract/Free Full Text]
- De Bosscher K, Schmitz ML, Vanden Berghe W, Plaisance S, Fiers W, and Haegeman G. Glucocorticoid-mediated repression of nuclear factor-kappaB-dependent transcription involves direct interference with transactivation. Proc Natl Acad Sci USA 94: 1350413509, 1997.[Abstract/Free Full Text]
- Evans RM and Hollenberg SM. Cooperative and positional independent trans-activation domains of the human glucocorticoid receptor. Cold Spring Harb Symp Quant Biol 53: 813818, 1988.[ISI][Medline]
- Falus A, Biro J, and Rakasz E. Cytokine networks and corticosteroid receptors. Ann NY Acad Sci 762: 7177, discussion 7778, 1995.[Abstract]
- Franchimont D, Martens H, Hagelstein MT, Louis E, Dewe W, Chrousos GP, Belaiche J, and Geenen V. Tumor necrosis factor alpha decreases, and interleukin-10 increases, the sensitivity of human monocytes to dexamethasone: potential regulation of the glucocorticoid receptor. J Clin Endocrinol Metab 84: 28342839, 1999.[Abstract/Free Full Text]
- Funder JW. Glucocorticoid and mineralocorticoid receptors: biology and clinical relevance. Annu Rev Med 48: 231240, 1997.[CrossRef][ISI][Medline]
- Hill MR, Stith RD, and McCallum RE. Human recombinant IL-1 alters glucocorticoid receptor function in Reuber hepatoma cells. J Immunol 141: 15221528, 1988.[Abstract/Free Full Text]
- Kam JC, Szefler SJ, Surs W, Sher ER, and Leung DY. Combination IL-2 and IL-4 reduces glucocorticoid receptor-binding affinity and T cell response to glucocorticoids. J Immunol 151: 34603466, 1993.[Abstract/Free Full Text]
- Kariagina A, Romanenko D, Ren SG, and Chesnokova V. Hypothalamic-pituitary cytokine network. Endocrinology 145: 104112, 2004.[Abstract/Free Full Text]
- Karin M and Chang L. AP-1glucocorticoid receptor crosstalk taken to a higher level. J Endocrinol 169: 447451, 2001.[Abstract/Free Full Text]
- Leung DY and Bloom JW. Update on glucocorticoid action and resistance. J Allergy Clin Immunol 111: 322, quiz 23, 2003.[CrossRef][ISI][Medline]
- Leung DY, de Castro M, Szefler SJ, and Chrousos GP. Mechanisms of glucocorticoid-resistant asthma. Ann NY Acad Sci 840: 735746, 1998.[Abstract/Free Full Text]
- McCormick JA, Lyons V, Jacobson MD, Noble J, Diorio J, Nyirenda M, Weaver S, Ester W, Yau JL, Meaney MJ, Seckl JR, and Chapman KE. 5'-heterogeneity of glucocorticoid receptor messenger RNA is tissue specific: differential regulation of variant transcripts by early-life events. Mol Endocrinol 14: 506517, 2000.[Abstract/Free Full Text]
- McIntyre WR and Samuels HH. Triamcinolone acetonide regulates glucocorticoid-receptor levels by decreasing the half-life of the activated nuclear-receptor form. J Biol Chem 260: 418427, 1985.[Abstract/Free Full Text]
- Otto C, Reichardt HM, and Schutz G. Absence of glucocorticoid receptor-beta in mice. J Biol Chem 272: 2666526668, 1997.[Abstract/Free Full Text]
- Pariante CM, Pearce BD, Pisell TL, Sanchez CI, Po C, Su C, and Miller AH. The proinflammatory cytokine, interleukin-1alpha, reduces glucocorticoid receptor translocation and function. Endocrinology 140: 43594366, 1999.[Abstract/Free Full Text]
- Reichardt HM, Kaestner KH, Tuckermann J, Kretz O, Wessely O, Bock R, Gass P, Schmid W, Herrlich P, Angel P, and Schutz G. DNA binding of the glucocorticoid receptor is not essential for survival. Cell 93: 531541, 1998.[CrossRef][ISI][Medline]
- Rosewicz S, McDonald AR, Maddux BA, Goldfine ID, Miesfeld RL, and Logsdon CD. Mechanism of glucocorticoid receptor down-regulation by glucocorticoids. J Biol Chem 263: 25812584, 1988.[Abstract/Free Full Text]
- Sapolsky RM, Romero LM, and Munck AU. How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. Endocr Rev 21: 5589, 2000.[Abstract/Free Full Text]
- Spencer RL, Kalman BA, Cotter CS, and Deak T. Discrimination between changes in glucocorticoid receptor expression and activation in rat brain using western blot analysis. Brain Res 868: 275286, 2000.[CrossRef][ISI][Medline]
- Verheggen MM, van Hal PT, Adriaansen-Soeting PW, Goense BJ, Hoogsteden HC, Brinkmann AO, and Versnel MA. Modulation of glucocorticoid receptor expression in human bronchial epithelial cell lines by IL-1 beta, TNF-alpha and LPS. Eur Respir J 9: 20362043, 1996.[Abstract/Free Full Text]
- Wallace AD and Cidlowski JA. Proteasome-mediated glucocorticoid receptor degradation restricts transcriptional signaling by glucocorticoids. J Biol Chem 276: 4271442721, 2001.[Abstract/Free Full Text]
- Wang Z, Ren SG, and Melmed S. Hypothalamic and pituitary leukemia inhibitory factor gene expression in vivo: a novel endotoxin-inducible neuro-endocrine interface. Endocrinology 137: 29472953, 1996.[Abstract]
- Waring PM, Waring LJ, and Metcalf D. Circulating leukemia inhibitory factor levels correlate with disease severity in meningococcemia. J Infect Dis 170: 12241228, 1994.[ISI][Medline]
- Webster JC and Cidlowski JA. Mechanisms of glucocorticoid-receptor-mediated repression of gene expression. Trends Endocrinol Metab 10: 396402, 1999.[CrossRef][ISI][Medline]
- Webster JC, Oakley RH, Jewell CM, and Cidlowski JA. Proinflammatory cytokines regulate human glucocorticoid receptor gene expression and lead to the accumulation of the dominant negative beta isoform: a mechanism for the generation of glucocorticoid resistance. Proc Natl Acad Sci USA 98: 68656870, 2001.[Abstract/Free Full Text]
- Weidenfeld J and Yirmiya R. Effects of bacterial endotoxin on the glucocorticoid feedback regulation of adrenocortical response to stress. Neuroimmunomodulation 3: 352357, 1996.[ISI][Medline]
- Yano H, Readhead C, Nakashima M, Ren SG, and Melmed S. Pituitary-directed leukemia inhibitory factor transgene causes Cushings syndrome: neuro-immune-endocrine modulation of pituitary development. Mol Endocrinol 12: 17081720, 1998.[Abstract/Free Full Text]
- Zhang Z, Jones S, Hagood JS, Fuentes NL, and Fuller GM. STAT3 acts as a co-activator of glucocorticoid receptor signaling. J Biol Chem 272: 3060730610, 1997.[Abstract/Free Full Text]
Copyright © 2005 by the American Physiological Society.