help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ren, S. G.
Right arrow Articles by Melmed, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ren, S. G.
Right arrow Articles by Melmed, S.
The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 8 2883-2887
Copyright © 1999 by The Endocrine Society

Original Studies

In Vivo and in Vitro Regulation of Thyroid Leukemia Inhibitory Factor (LIF): Marker of Hypothyroidism1

Song Guang Ren, Judy Seliktar, Xian Li, Jerome M. Hershman, Glenn D. Braunstein and Shlomo Melmed

Department of Medicine (S.G.R., J.S., X.L., G.D.B., S.M.), Cedars-Sinai Research Institute; Endocrine Research Laboratory West Los Angeles (J.M.H.), VA Medical Center; UCLA School of Medicine, Los Angeles, California 90048

Address all correspondence and requests for reprints to: Shlomo Melmed, M.D., Division of Endocrinology & Metabolism, Cedars-Sinai Medical Center, 8700 Beverly Blvd; Room B-131, Los Angeles, California 90048. E-mail: melmed{at}csmc.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Several cytokines regulate thyroid function and may be involved in the pathogenesis of thyroid disorders, including euthyroid sick syndrome. Leukemia inhibitory factor (LIF), a neuroimmune pleiotropic cytokine, was measured to assess its role in hypothalamic-pituitary-thyroid function. Mean circulating serum LIF levels in 10 hypothyroid patients [TSH, 23 ± 0.5 mIU/L (mean ± SEM); free T4, 0.77 ± 0.1 ng/dL] was 0.29 ± 0.04 ng/mL, 145% higher (P < 0.04) than in 20 normal subjects (LIF, 0.20 ± 0.02 ng/mL; TSH, 2.23 ± 0.21 mIU/L; free T4, 1.23 ± 0.04 ng/dL) but was not different from those in 10 hyperthyroid patients (LIF, 0.21 ± 0.03 ng/mL; TSH, 0.01 ± 0.00 mIU/L; free T4, 3.63 ± 0.51 ng/dL). Serum LIF concentrations linearly correlated with serum TSH in the 40 samples (r = 0.58, P < 0.001). When T4 (1–8 µg/kg·day) was administered to cynomolgus monkeys with methimazole-induced hypothyroidism, serum T4 and T3 levels increased appropriately, and TSH and LIF concentrations decreased. When methimazole was given alone, both serum TSH (146 ± 30 mIU/L) and LIF (8.84 ± 0.49 ng/mL) were markedly induced. When methimazole together with T4 (>2 µg/kg·day) was administered, both serum TSH (7.5 ± 1.2 mIU/L) and LIF (6.22 ± 0.31 ng/mL) were lowered (P < 0.01). Monkey serum LIF levels and log TSH levels also correlated (r = 0.72, P < 0.01). Cultured thyroid carcimona cells produced LIF (9.2 ng/106 cells/48 h). TSH (100 mIU/mL) and interleukin (IL)-6 (10 nmol/L) stimulated in vitro LIF secretion from the cells by 170 ± 12% (P < 0.05) and 261 ± 8% (P < 0.05), respectively. Dexamethasone (1 µmol/L) inhibited basal LIF concentration by 83% (P < 0.05), whereas TSH and IL-6 stimulated LIF by 52% (P = 0.04) and 42% (P = 0.03), respectively. However, using Northern blot analysis, we could not observe induction of LIF mRNA by TSH, suggesting that LIF regulation by TSH may be due to stimulation of secretion. The results show that the thyroid gland is a source of LIF production; TSH, IL-6, and glucocorticoid influence thyroid cell LIF expression. The correlation between TSH and LIF suggests that LIF may participate in the physiologic regulation of hypothalamic-pituitary-thyroid function.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
CYTOKINES are soluble polypeptides released from several cell types, especially those derived from the immune system. Accumulating evidence indicates that many cytokines are synthesized and secreted within endocrine glands and affect hormone-secreting cells (1, 2). Human thyrocytes express interleukin (IL)-6 messenger RNA (mRNA) and release IL-6, which in turn affects the hypothalamic-pituitary-thyroid axis (3). Other cytokines, such as IL-1, tumor necrosis factor (TNF)-{alpha}, and oncostatin M (OSM) have been reported to inhibit thyroid function (3, 4, 5).

Leukemia inhibitory factor (LIF) is an important member of the cytokine family (6). Our previous studies have shown that human and murine pituitary cells express the LIF gene and LIF-binding sites (7, 8), and LIF synergizes with CRH induction of POMC transcription, resulting in a striking increase in ACTH secretion from pituitary cells in vitro, as well as in vivo (8, 9, 10).

In this study, we assessed the role of LIF in hypothalamic-pituitary-thyroid function, including an examination of LIF production and regulation in isolated thyrocytes.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Human subjects

Blood samples were obtained from normal subjects and hypothyroid or hyperthyroid patients before treatment. Serum was stored at -20 C until assay for LIF, TSH, free T4, and T3 levels.

Primate studies

Monkey sera were obtained from a previous study of thyroid function (11). Briefly, after 12 weeks of baseline studies, five male and five female cynomolgus monkeys, 2–2.5 yr old, were rendered hypothyroid by addition of 0.0125% methimazole to their drinking water for the ensuing duration of the study. After 12 weeks of methimazole administration, each animal received exogenous T4 (1, 2, 4, or 8 µg/kg·day), for 9 weeks, with intervals of 6 weeks between successive T4 doses. Blood was collected every 3 weeks during the baseline period, the methimazole-only period, and each T4 dose treatment period. Results from serum assayed during each baseline and treatment period were individually averaged to obtain the mean level during the corresponding period for each animal. Serum was stored at -20 C until assays for TSH, T4, T3, and LIF levels.

Cell culture

A human thyroid carcinoma cell line BHP 18 (12) was cultured in 6-multiwell culture plates or 75-cm2 flasks (Life Technologies, Gaithersburg, MD) containing RPMI-1640 medium (Life Technologies) supplied with 10% FBS and antibiotics. When cells were confluent, medium was removed, and cells were exposed, for an additional 48 h, to serum-free RPMI-1640 medium containing either 0.1% ethanol or 1 µmol/L dexamethasone (dissolved in ethanol; final concentration of ethanol was 0.1%), without or with 100 mU/mL TSH (Sigma Chemical Co., St. Louis, MO) or 10 nmol/L IL-6 (R&D Systems, Minneapolis, MN). At the end of the experiment, the medium was removed, centrifuged, and stored at -20 C until assay. Cells were then counted or RNA extracted.

LIF measurement

LIF, in serum or culture medium, was measured in duplicate by RIA, as previously described (13). Escherichia coli-derived recombinant human (h)LIF and goat polyclonal anti-hLIF antibody were purchased (R&D Systems), and LIF was iodinated using an iodogen (Pierce Chemical Co., Rockford, IL) method (14). The sensitivity was 0.05 ng/mL. Intraassay variations were 7% at 50 ng/mL and 4% at 6 ng/mL. Interassay variations were 3% at 50 ng/mL and 11% at 6 ng/mL. As we previously mentioned, LIF standard is not available and LIF levels measured by this RIA should be considered relative immunoreactive values (13); therefore, LIF values for comparison in each group were measured in a single assay. Serial dilutions of monkey serum were assayed by hLIF RIA, and the observed LIF values were parallel to the human standard curve (r = 0.996, P < 0.004), indicating that the hLIF RIA measured immunoreactive LIF in monkey serum.

TSH, thyroid hormones measurement

Human serum TSH, free T4, and total T3 values were measured with the IMX System using the microparticle enzyme immunoassay technology of Abbott Laboratories (Abbott Park, IL), as previously described (15, 16). Monkey serum TSH, T4, and T3 levels were measured in duplicate by RIA at Hazleton Laboratories (Vienna, VA), as previously described (11). Human TSH as standard and labeled ligand and antihuman-TSH serum were used in the TSH RIA, which recognized monkey TSH.

Northern blot

LIF gene expression in the thyroid carcinoma cell line was measured by Northern blot method, as previously described (7). The BamHI-HindIII fragment of hLIF complementary DNA was kindly provided by Dr. Tracy Willson of The Walter Eliza Hall Institute of Medical Research, Melbourne, Australia.

Statistics

Results are expressed as mean ± SEM. Student’s t test was used to compare results, and correlation coefficients were determined by linear regression analysis.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Mean circulating serum LIF levels in 10 hypothyroid patients was 0.29 ± 0.04 ng/mL, 145% higher (P < 0.05) than in 20 normal subjects (0.20 ± 0.02 ng/mL) but not different from values in 10 hyperthyroid patients (0.21 ± 0.03 ng/mL). Serum TSH, free T4, T3, and LIF concentrations in 3 groups are listed in Table 1Go. Serum LIF concentrations correlated with serum TSH levels in the 40 samples (r = 0.58, P < 0.001), as shown in Fig. 1Go, but did not correlate with free T4 or T3 levels. The correlation coefficients between free T4 and T3 was 0.89 (P < 0.001); and between free T4 and TSH, it was -0.35 (P = 0.011).


View this table:
[in this window]
[in a new window]
  		Table 1. Serum LIF, TSH, Free T4, and T3 levels in patients with altered thyroid function

 


View larger version (10K):
[in this window]
[in a new window]
  		Figure 1. Linear regression of serum LIF concentrations with serum TSH levels in 40 human subjects (r = 0.58, P < 0.001).

 
In the monkey study, when methimazole was given alone, both serum LIF and TSH were markedly increased (by 130% and 2300%, respectively), and T4 and T3 levels were significantly reduced, compared with baseline. When T4 (1–8 µg/kg·day) was administered to cynomolgus monkeys with methimazole-induced hypothyroidism, serum T4 and T3 levels increased appropriately, and TSH and LIF concentrations decreased. When the exogenous T4 dose was greater than 2 µg/kg·day, both serum LIF and TSH levels were reduced, respectively, to 70 and 5% of values observed during hypothyroidism. The dose-response relationships between the exogenous T4 dose and the serum LIF, TSH, T4, and T3 levels are shown in Table 2Go. Mean serum LIF levels and TSH levels during each period also correlated (r = 0.72, P < 0.01) (Fig. 2Go).


View this table:
[in this window]
[in a new window]
  		Table 2. Dose-response relationships between T4 administration and monkey serum LIF, TSH, T4 and T3 levels

 


View larger version (7K):
[in this window]
[in a new window]
  		Figure 2. Linear regression of mean serum LIF and log TSH levels in male and female monkeys during baseline, methimazole alone, or 1, 2, 4, and 8 µg/kg·day of exogenous T4 with methimazole administered (r = 0.72, P < 0.01).

 
Cultured thyroid carcinoma cells produced 9.2 ng LIF/106 cells·48 h. TSH (100 mIU/mL) and IL-6 (10 nmol/L) stimulated in vitro LIF secretion from the cells by 170 ± 12% (P < 0.05) and 261 ± 8% (P < 0.05), respectively. Dexamethasone (1 µmol/L) inhibited basal LIF concentration by 53%, whereas TSH and IL-6 stimulated LIF by 52% (P < 0.05) and 42% (P < 0.05), respectively, as shown in Fig. 3Go.



View larger version (13K):
[in this window]
[in a new window]
  		Figure 3. Regulation of hLIF production in human thyroid carcinoma cells. Cells were exposed for 48 h to serum-free medium containing either 0.1% ethanol (open bar) or 1 µmol/L dexamethasone (Dex, black bar), without or with either 100 mU/mL TSH or 10 nmol/L IL-6. LIF in the culture medium was measured by hLIF RIA. Data are expressed as mean ± SEM of 14 wells in three experiments. *, P < 0.05 vs. control; **, P < 0.05 vs. culture medium containing 01% ethanol.

 
Northern blot analysis indicated that LIF was expressed in the thyroid cell line, but not regulated by a wide range of TSH examined at different time points, suggesting that TSH may stimulate LIF-secretion but not its synthesis.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The results indicate that hypothyroidism is associated with elevated serum LIF levels. Untreated hypothyroid patients had significantly higher serum LIF levels than normal subjects (Table 1Go). Serum LIF levels in monkeys with methimazole-induced hypothyroidism were markedly elevated, compared with normal, and this increase in LIF concentration was reversed with exogenous T4 doses greater than 2µg/kg·day (Table 2Go). Hyperthyroidism, however, is not associated with either higher or lower serum LIF levels in humans. When 8 µg/kg·day T4 was given to monkeys, TSH was markedly reduced, T3 and T4 were significantly increased (compared with baseline), but serum LIF did not differ from baseline (Table 2Go).

From our data, however, we could not determine the initial abnormality in LIF, TSH, and thyroid hormones that results in high serum LIF and TSH levels and low thyroid hormone concentrations. The reason for high serum LIF levels in hypothyroidism remains unclear. One explanation is that low thyroid hormone levels induced TSH, which stimulated thyroid LIF release. Therefore, elevated serum LIF concentrations, observed in hypothyroid patients and monkeys, may be caused by enhanced LIF secretion from thyroid cells stimulated by TSH. This hypothesis is suggested by the significant correlation between serum LIF and TSH levels in both patients and monkeys (Figs. 1Go and 2Go) and the stimulation by TSH of LIF secretion from human thyroid carcinoma cells (Fig. 3Go). Our results detecting LIF production in thyroid cells and its stimulation by TSH are similar to those of studies with IL-6, which has been shown to be produced by the thyroid gland (3) and stimulated by TSH (17). However, this hypothesis should be further confirmed by testing in more thyroid cell lines with a wide range of TSH doses. Nevertheless, TSH seems to be an LIF regulator, because low levels of TSH seen in hyperthyroidism did not alter mean serum LIF levels, compared with baseline.

Alternatively, high LIF levels may inhibit thyroid hormone production, which, in turn, induces TSH secretion. Although our data could not directly support this hypothesis, studies on other members of the related family of pleiotropic cytokines (including OSM, IL-6, and IL-11) provided indirect evidence. Although these individual cytokines have unique biological functions, they also have common functions and share a common signal transducer gp-130 (1, 2, 5, 18). For example, IL-6 suppresses thyroid peroxidase gene expression and T3 secretion from cultured human thyrocytes (19), and administration of IL-6 into humans decreases plasma T3 concentrations (20). In an investigation of 270 hospital inpatients with nonthyroidal illness, a significant negative correlation between serum total T3 and IL-6, and total T4 and IL-6 were observed (21). IL-6 also may decrease TSH levels in vivo (20, 21). Furthermore, TNF inhibited thyroid function (4), and decreased serum T3 levels and decreased serum free T4 levels were associated with increased circulating levels of TNF in nonthyroid disease patients (22, 23). Recently, OSM and IL-6, as well as LIF, were shown to inhibit iodide uptake stimulated by TSH in cultured thyroid cells (5). Using a RT-PCR technique, gp-130 and LIF receptor ß-subunit mRNA were detected in porcine thyroid cells (5). Together, these data suggest that LIF may function to suppress thyroid hormone production. In our study, however, thyroid hormone synthesis in monkey thyroid was initially inhibited by methimazole, followed by increases of LIF and TSH levels. Therefore, even if LIF has any inhibitory action on thyroid hormone production, it should be considered as a secondary-effect-mediated autocrine mechanism.

Another possibility is that LIF synthesis is under negative feedback control by thyroid hormone and low levels of thyroid hormone releases the inhibition of LIF, as well as TSH, resulting in elevated concurrent LIF and TSH production. LIF is produced from multiple cell types, including endometrium, bone marrow stromal, thymic, lymphocytes, pituitary, and thyroid (2, 24, 25), and thyroid hormone functions in multiple cell types. It is unknown whether thyroid hormone inhibits LIF production from these cells. Although the pituitary is a known source of LIF (7, 24), the concentrations are in picogram quantities per pituitary (13), whereas the thyroid cells produce nanogram quantities of LIF, making it more likely that the thyroid (not the pituitary) is the source of serum LIF in this study. Our unpublished data also showed that T4 (10 µg/mL) could not inhibit LIF production in the BHP 18 human thyroid carcinoma cell line.

LIF is cleared rapidly from the circulation. Studies showed that murine LIF injected ip into adult mice has an initial half-life of 6–8 min and a prolonged secondary clearance phase of several hours. The clearance of murine LIF from the circulation is paralleled by accumulation of LIF in the kidneys, liver, lung, spleen, and thyroid gland; and kidneys are the major route of LIF clearance (26). Patients with hypothyroidism have low metabolic rates. Therefore, it is also possible that the clearance rate of LIF in hypothyroidism patients is slower, resulting in higher serum LIF levels.

Previous studies have shown that IL-1{alpha}, IL-1ß, or TNF-{alpha} induces LIF gene expression in fibroblasts (27), bone marrow cells (28), endometrial cells (29), and pituitary cells (30). It also has been reported that LIF gene expression is stimulated by IL-6 (6) and inhibited by dexamethasone in rat anterior pituitary (31). The results shown here indicate that regulation of LIF by these agents also occurs in the thyroid gland.

In summary, our results indicate that the thyroid gland is a source of LIF production and that IL-6, glucocorticoids, and TSH influence LIF secretion in cultured thyroid cells. Moreover, the strong correlation between serum TSH and LIF levels suggests that LIF may be involved in the physiology and pathology of hypothalamic-pituitary-thyroid function.


   Acknowledgments
 
We would like to thank Drs. Saul Malozowski S, Chiara Simoni, Hernan Garcia, Manuela Caruso-Nicoletti, Gordon B. Cutler, and Fernando Cassorla for their assistance in the monkey study; Ms. Loretta Berg for collecting blood samples and maintenance of thyroid carcinoma cells; and Grace Labrado for preparing the manuscript.


   Footnotes
 
1 This work was supported by NIH Grant DK-42792 and the Doris Factor Molecular Endocrinology Laboratory. Back

Received January 21, 1998.

Revised May 7, 1998.

Revised May 7, 1999.

Accepted May 13, 1999.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Besedovsky HO, Rey AD. 1996 Immune-neuro-endocrine interactions: facts and hypotheses. Endocr Rev. 17:64–102.[Abstract/Free Full Text]
  2. Auernhammer C, Bousquet C, Melmed S. 1999 Proc Natl Acad Sci USA. 96:6964–6969.[Abstract/Free Full Text]
  3. Jones TH. 1994 Interleukin-6 an endocrine cytokine. Clin Endocrinol (Oxf). 40:703–713.[Medline]
  4. Hershman JM, Pang XP. 1991 Tumor necrosis factor-alpha and the pituitary-thyroid axis. In: Melmed S, Robbins RJ, eds. Molecular and clinical advances in pituitary disorders. Blackwell Scientific Publications; 153–169.
  5. Isozaki O, Tsushima T, Miyakawa M, et al. 1997 Oncostatin M, a new potent inhibitor of iodine metabolism, inhibits thyroid peroxidase gene expression but not DNA synthesis in porcine thyroid cells in culture. Thyroid. 7:71–77.[Medline]
  6. Kurzrock R, Estrov Z, Wetzler M, Gutterman JU, Talpaz M. 1991 LIF: not just a leukemia inhibitory factor. Endocr Rev. 12:208–217.[Abstract/Free Full Text]
  7. Akita S, Webster J, Ren SG, et al. 1995 Human and murine pituitary expression of leukemia inhibitory factor: novel intrapituitary regulation of adrenocorticotropin hormone synthesis and secretion. J Clin Invest. 95:1288–1298.
  8. Wang ZY, Ren SG, Melmed S. 1996 Hypothalamic and pituitary leukemia inhibitory factor gene expression in vivo: a novel endotoxin-inducible neuro-endocrine interface. Endocrinology. 137:2947–2953.[Abstract]
  9. Akita S, Malkin J, Melmed S. 1996 Disrupted murine leukemia inhibitory factor (LIF) gene attenuates adrenocorticotropic hormone (ACTH) secretion. Endocrinology. 137:3140–3143.[Abstract]
  10. Ray DW, Ren SG, Melmed S. 1996 Leukemia inhibitory factor (LIF) stimulates proopopmelanocortin (POMC) expression in a corticotroph cell line. J Clin Invest. 97:1852–1859.[Medline]
  11. Ren SG, Malozowski S, Simoni C, et al. 1988 Dose-response relationship between thyroid hormone and growth velocity in cynomolgus monkeys. J Clin Endocrinol Metab. 66:1010–1013.[Abstract/Free Full Text]
  12. Ohta K, Pang XP, Berg L, Hershman JM. 1996 Antitumor actions of cytokines on new human papillary thyroid carcinoma cell lines. J Clin Endocrinol Metab. 81:2607–2612.[Abstract]
  13. Ren SG, Seliktar J, Li X, Braunstein GD, Melmed S. 1998 Measurement of leukemia inhibitory factor in biological fluid by radioimmunoassay. J Clin Endocrinol Metab 83:1275–1283.
  14. Salacinski PBP, Mclean C, Sykes JEC, Ciimini-Jones VV, Lowry PJ. 1981 Iodination of proteins, glycoproteins, and peptide using a solid-phase oxidizing agent, 1,3,4,6-tetracholoro-3,6-diphenyl glycoluril (iodogen). Anal Biochem. 117:136–146.[CrossRef][Medline]
  15. Hershman JM, Pekary AE, Berg L, Solomon DH, Sawin CT. 1993 Serum thyrotropin and thyroid hormone levels in elderly and middle-aged euthyroid persons. J Am Geriatr Soc. 41:823–828.[Medline]
  16. Wong TK, Pekary AE, Hoo GS, Bradley ME, Hershman JM. 1992 Comparison of methods for measuring free thyroxin in nonthyroidal illness. Clin Chem. 38:720–724.[Abstract/Free Full Text]
  17. Kennedy RL, Jones TH, Davies R, Justice SK, Lemoine NR. 1992 Release of interleukin-6 by human thyroid epithelial cells immortalized by simian virus 40 DNA transfection. J Endocrinol. 133:477–482.[Abstract/Free Full Text]
  18. Shimon I, Yan XM, Ray DW, Melmed S. 1997 Cytokine-dependent gp-130 receptor subunit regulates human fetal pituitary adrenocorticotropin hormone and growth hormone secretion. J Clin Invest. 100:357–363.[Medline]
  19. Tominaga T, Yamashita S, Nagayama Y, et al. 1991 Interleukin 6 inhibits human thyroid peroxidase expression. Acta Endocrinol (Copenh). 124:290–294.[Abstract/Free Full Text]
  20. Stouthard JML, Poll T, Endert E, et al. 1994 Effects of acute and chronic interleukin-6 administration on thyroid hormone metabolism in humans. J Clin Endocrinol Metab. 79:1342–1346.[Abstract]
  21. Davies PH, Black EG, Sheppard MC, Franklyn JA. 1996 Relation between serum interleukin-6 and thyroid hormone concentrations in 270 hospital in-patients with non-thyroidal illness. Clin Endocrinol (Oxf). 44:199–205.[CrossRef][Medline]
  22. Mooradian AD, Reed RL, Osterweil D, Schiffman R, Scuderi P. 1990 Decreased serum triiodothyronine is associated with increased concentrations of tumor necrosis factor. J Clin Endocrinol Metab. 71:1239–1242.[Abstract/Free Full Text]
  23. Wong TK, Pekary AE, Soo Hoo G, Bradley ME, Hershman JM. 1992 Comparison of methods for measuring free thyroxin in nonthyroidal illness. Clin Chem. 38:720–724.
  24. Kurzrock R, Estrov Z, Wetzier M, Gutterman JU, Taipaz M. 1991 LIF: Not just a leukemia inhibitory factor. Endocr Rev. 12:208–217.
  25. Fukada K, Korsching S, Towel MF. 1997 Tissue-specific and ontogenetic regulation of LIF protein levels determines by quantitative enzyme immunoassay. Growth Factors. 14:279–295.[Medline]
  26. Hilton DL, Nicola NA, Waring PM, Metcalf D. 1991 Clearance and fate of leukemia-inhibitory factor (LIF) after injection into mice. J Cell Physiol. 148:430–439.[CrossRef][Medline]
  27. Hamilton J, Waring P, Filonzi E. 1993 Induction of leukemia inhibitory factor in human synovial fibroblast by IL-1 and tumor necrosis factor-{alpha}. J Immunol. 150:1496–1502.[Abstract]
  28. Derigs H, Boswell H. 1993 LIF mRNA expression is transcriptionally regulated in murine bone marrow stromal cells. Leukemia. 7:630–634.[Medline]
  29. Arici A, Engin O, Attar E, Olive D. 1994 Modulation of leukemia inhibitory factor gene expression and protein biosynthesis in human endometrium. J Clin Endocrinol Metab. 80:1908–1915.[Abstract]
  30. Auernhammer CJ, Chesnokova V, Melmed S. 1998 Leukemia inhibitory factor (LIF) modulates IL-1ß induced activation of the hypothalamo-pituitary-adrenal axis. Endocrinology. 139:2201–2208.[Abstract/Free Full Text]
  31. Carter DA. 1995 Leukaemia inhibitory factor expression in cultured rat anterior pituitary is regulated by glucocorticoids. J Neuroendocrinology. 7:623–628.[CrossRef][Medline]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ren, S. G.
Right arrow Articles by Melmed, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ren, S. G.
Right arrow Articles by Melmed, S.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals