Human and murine pituitary expression of leukemia inhibitory factor. Novel intrapituitary regulation of adrenocorticotropin hormone synthesis and secretion (original) (raw)

Abstract

Leukemia inhibitory factor (LIF) gene expression was detected in human fetal pituitary tissue by expression of LIF mRNA transcripts, protein immunocytochemistry, and immunoelectron microscopy. Fetal LIF immunoreactivity colocalized with 30% of ACTH-expressing cells, approximately 20% of somatotrophs, and approximately 15% of non-hormone-expressing cells. LIF was also strongly expressed in normal adult pituitary and in four growth hormone-producing and two ACTH-producing adenomas, but not in eight nonfunctioning pituitary tumors. Culture of fetal cells expressing surface LIF-binding sites demonstrated predominance of in vitro ACTH secretion as compared with other pituitary hormones. In AtT-20 murine cells, LIF (ED50 10 pM) stimulated basal proopiomelanocortin mRNA levels by 40% and corticotropin-releasing hormone-induced ACTH secretion (two- to threefold), as did oncostatin M (ED50 30 pM), a related peptide. ACTH responses were not further enhanced by both cytokines together, which is consistent with their shared receptor. Anti-LIF antiserum neutralized basal and LIF-induced ACTH secretion, suggesting autocrine regulation of ACTH by LIF. The results show that human pituitary cells express the LIF gene and LIF-binding sites, predominantly in corticotrophs. Pituitary LIF expression and LIF regulation of proopiomelanocortin and ACTH reflect an intrapituitary role for LIF in modulating early embryonic determination of specific human pituitary cells and as a paracrine or autocrine regulator of mature ACTH.

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  1. Arzt E., Buric R., Stelzer G., Stalla J., Sauer J., Renner U., Stalla G. K. Interleukin involvement in anterior pituitary cell growth regulation: effects of IL-2 and IL-6. Endocrinology. 1993 Jan;132(1):459–467. doi: 10.1210/endo.132.1.8419142. [DOI] [PubMed] [Google Scholar]
  2. Arzt E., Stelzer G., Renner U., Lange M., Müller O. A., Stalla G. K. Interleukin-2 and interleukin-2 receptor expression in human corticotrophic adenoma and murine pituitary cell cultures. J Clin Invest. 1992 Nov;90(5):1944–1951. doi: 10.1172/JCI116072. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Asa S. L., Kovacs K. Functional morphology of the human fetal pituitary. Pathol Annu. 1984;19(Pt 1):275–315. [PubMed] [Google Scholar]
  4. Asa S. L., Kovacs K., Singer W. Human fetal adenohypophysis: morphologic and functional analysis in vitro. Neuroendocrinology. 1991 Jun;53(6):562–572. doi: 10.1159/000125775. [DOI] [PubMed] [Google Scholar]
  5. Baird A., Mormède P., Ying S. Y., Wehrenberg W. B., Ueno N., Ling N., Guillemin R. A nonmitogenic pituitary function of fibroblast growth factor: regulation of thyrotropin and prolactin secretion. Proc Natl Acad Sci U S A. 1985 Aug;82(16):5545–5549. doi: 10.1073/pnas.82.16.5545. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Baker B. L., Jaffe R. B. The genesis of cell types in the adenohypophysis of the human fetus as observed with immunocytochemistry. Am J Anat. 1975 Jun;143(2):137–161. doi: 10.1002/aja.1001430202. [DOI] [PubMed] [Google Scholar]
  7. Bernton E. W., Beach J. E., Holaday J. W., Smallridge R. C., Fein H. G. Release of multiple hormones by a direct action of interleukin-1 on pituitary cells. Science. 1987 Oct 23;238(4826):519–521. doi: 10.1126/science.2821620. [DOI] [PubMed] [Google Scholar]
  8. Blumenfeld Z., Jaffe R. B. Hypophysiotropic and neuromodulatory regulation of adrenocorticotropin in the human fetal pituitary gland. J Clin Invest. 1986 Jul;78(1):288–294. doi: 10.1172/JCI112563. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Boyle M., Yamamoto G., Chen M., Rivier J., Vale W. Interleukin 1 prevents loss of corticotropic responsiveness to beta-adrenergic stimulation in vitro. Proc Natl Acad Sci U S A. 1988 Aug;85(15):5556–5560. doi: 10.1073/pnas.85.15.5556. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Chen R., Lewis K. A., Perrin M. H., Vale W. W. Expression cloning of a human corticotropin-releasing-factor receptor. Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):8967–8971. doi: 10.1073/pnas.90.19.8967. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Childs G. V., Lloyd J., Unabia G., Rougeau D. Growth and secretory responses of enriched populations of corticotropes. Endocrinology. 1989 Nov;125(5):2540–2549. doi: 10.1210/endo-125-5-2540. [DOI] [PubMed] [Google Scholar]
  12. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  13. Cohen C. B., Jonsen A. R. The future of the fetal tissue bank. The National Advisory Board on Ethics in Reproduction. Science. 1993 Dec 10;262(5140):1663–1665. doi: 10.1126/science.8259510. [DOI] [PubMed] [Google Scholar]
  14. Davis S., Aldrich T. H., Stahl N., Pan L., Taga T., Kishimoto T., Ip N. Y., Yancopoulos G. D. LIFR beta and gp130 as heterodimerizing signal transducers of the tripartite CNTF receptor. Science. 1993 Jun 18;260(5115):1805–1808. doi: 10.1126/science.8390097. [DOI] [PubMed] [Google Scholar]
  15. Fagin J. A., Brown A., Melmed S. Regulation of pituitary insulin-like growth factor-I messenger ribonucleic acid levels in rats harboring somatomammotropic tumors: implications for growth hormone autoregulation. Endocrinology. 1988 May;122(5):2204–2210. doi: 10.1210/endo-122-5-2204. [DOI] [PubMed] [Google Scholar]
  16. Ferrara N., Schweigerer L., Neufeld G., Mitchell R., Gospodarowicz D. Pituitary follicular cells produce basic fibroblast growth factor. Proc Natl Acad Sci U S A. 1987 Aug;84(16):5773–5777. doi: 10.1073/pnas.84.16.5773. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Ferrara N., Winer J., Henzel W. J. Pituitary follicular cells secrete an inhibitor of aortic endothelial cell growth: identification as leukemia inhibitory factor. Proc Natl Acad Sci U S A. 1992 Jan 15;89(2):698–702. doi: 10.1073/pnas.89.2.698. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Fukata J., Usui T., Naitoh Y., Nakai Y., Imura H. Effects of recombinant human interleukin-1 alpha, -1 beta, 2 and 6 on ACTH synthesis and release in the mouse pituitary tumour cell line AtT-20. J Endocrinol. 1989 Jul;122(1):33–39. doi: 10.1677/joe.0.1220033. [DOI] [PubMed] [Google Scholar]
  19. Gearing D. P., Comeau M. R., Friend D. J., Gimpel S. D., Thut C. J., McGourty J., Brasher K. K., King J. A., Gillis S., Mosley B. The IL-6 signal transducer, gp130: an oncostatin M receptor and affinity converter for the LIF receptor. Science. 1992 Mar 13;255(5050):1434–1437. doi: 10.1126/science.1542794. [DOI] [PubMed] [Google Scholar]
  20. Gearing D. P., Gough N. M., King J. A., Hilton D. J., Nicola N. A., Simpson R. J., Nice E. C., Kelso A., Metcalf D. Molecular cloning and expression of cDNA encoding a murine myeloid leukaemia inhibitory factor (LIF). EMBO J. 1987 Dec 20;6(13):3995–4002. doi: 10.1002/j.1460-2075.1987.tb02742.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Gertz B. J., Contreras L. N., McComb D. J., Kovacs K., Tyrrell J. B., Dallman M. F. Chronic administration of corticotropin-releasing factor increases pituitary corticotroph number. Endocrinology. 1987 Jan;120(1):381–388. doi: 10.1210/endo-120-1-381. [DOI] [PubMed] [Google Scholar]
  22. Gough N. M., Gearing D. P., King J. A., Willson T. A., Hilton D. J., Nicola N. A., Metcalf D. Molecular cloning and expression of the human homologue of the murine gene encoding myeloid leukemia-inhibitory factor. Proc Natl Acad Sci U S A. 1988 Apr;85(8):2623–2627. doi: 10.1073/pnas.85.8.2623. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Gwosdow A. R., O'Connell N. A., Abou-Samra A. B. Interleukin-1 increases protein kinase A activity by a cAMP-independent mechanism in AtT-20 cells. Am J Physiol. 1994 Jan;266(1 Pt 1):E79–E84. doi: 10.1152/ajpendo.1994.266.1.E79. [DOI] [PubMed] [Google Scholar]
  24. Harbuz M. S., Rees R. G., Eckland D., Jessop D. S., Brewerton D., Lightman S. L. Paradoxical responses of hypothalamic corticotropin-releasing factor (CRF) messenger ribonucleic acid (mRNA) and CRF-41 peptide and adenohypophysial proopiomelanocortin mRNA during chronic inflammatory stress. Endocrinology. 1992 Mar;130(3):1394–1400. doi: 10.1210/endo.130.3.1537299. [DOI] [PubMed] [Google Scholar]
  25. Hilton D. J., Nicola N. A., Metcalf D. Specific binding of murine leukemia inhibitory factor to normal and leukemic monocytic cells. Proc Natl Acad Sci U S A. 1988 Aug;85(16):5971–5975. doi: 10.1073/pnas.85.16.5971. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Hinkle P. M., Shanshala E. D., 2nd, Yan Z. F. Epidermal growth factor decreases the concentration of thyrotropin-releasing hormone (TRH) receptors and TRH responses in pituitary GH4C1 cells. Endocrinology. 1991 Sep;129(3):1283–1288. doi: 10.1210/endo-129-3-1283. [DOI] [PubMed] [Google Scholar]
  27. Imura H., Fukata J. Endocrine-paracrine interaction in communication between the immune and endocrine systems. Activation of the hypothalamic-pituitary-adrenal axis in inflammation. Eur J Endocrinol. 1994 Jan;130(1):32–37. doi: 10.1530/eje.0.1300032. [DOI] [PubMed] [Google Scholar]
  28. Jones T. H., Justice S., Price A., Chapman K. Interleukin-6 secreting human pituitary adenomas in vitro. J Clin Endocrinol Metab. 1991 Jul;73(1):207–209. doi: 10.1210/jcem-73-1-207. [DOI] [PubMed] [Google Scholar]
  29. Kishimoto T., Taga T., Akira S. Cytokine signal transduction. Cell. 1994 Jan 28;76(2):253–262. doi: 10.1016/0092-8674(94)90333-6. [DOI] [PubMed] [Google Scholar]
  30. Kobrin M. S., Asa S. L., Samsoondar J., Kudlow J. E. Alpha-transforming growth factor in the bovine anterior pituitary gland: secretion by dispersed cells and immunohistochemical localization. Endocrinology. 1987 Oct;121(4):1412–1416. doi: 10.1210/endo-121-4-1412. [DOI] [PubMed] [Google Scholar]
  31. Koenig J. I., Snow K., Clark B. D., Toni R., Cannon J. G., Shaw A. R., Dinarello C. A., Reichlin S., Lee S. L., Lechan R. M. Intrinsic pituitary interleukin-1 beta is induced by bacterial lipopolysaccharide. Endocrinology. 1990 Jun;126(6):3053–3058. doi: 10.1210/endo-126-6-3053. [DOI] [PubMed] [Google Scholar]
  32. Kudlow J. E., Kobrin M. S. Secretion of epidermal growth factor-like mitogens by cultured cells from bovine anterior pituitary glands. Endocrinology. 1984 Sep;115(3):911–917. doi: 10.1210/endo-115-3-911. [DOI] [PubMed] [Google Scholar]
  33. Lecron J. C., Roblot P., Chevalier S., Morel F., Alderman E., Gombert J., Gascan H. High circulating leukaemia inhibitory factor (LIF) in patients with giant cell arteritis: independent regulation of LIF and IL-6 under corticosteroid therapy. Clin Exp Immunol. 1993 Apr;92(1):23–26. doi: 10.1111/j.1365-2249.1993.tb05942.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Lee J. J., Costlow N. A. A molecular titration assay to measure transcript prevalence levels. Methods Enzymol. 1987;152:633–648. doi: 10.1016/0076-6879(87)52070-5. [DOI] [PubMed] [Google Scholar]
  35. Low M. J., Liu B., Hammer G. D., Rubinstein M., Allen R. G. Post-translational processing of proopiomelanocortin (POMC) in mouse pituitary melanotroph tumors induced by a POMC-simian virus 40 large T antigen transgene. J Biol Chem. 1993 Nov 25;268(33):24967–24975. [PubMed] [Google Scholar]
  36. Metcalf D., Gearing D. P. Fatal syndrome in mice engrafted with cells producing high levels of the leukemia inhibitory factor. Proc Natl Acad Sci U S A. 1989 Aug;86(15):5948–5952. doi: 10.1073/pnas.86.15.5948. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Metcalf D. Leukemia inhibitory factor--a puzzling polyfunctional regulator. Growth Factors. 1992;7(3):169–173. doi: 10.3109/08977199209046921. [DOI] [PubMed] [Google Scholar]
  38. Muramami N., Fukata J., Tsukada T., Kobayashi H., Ebisui O., Segawa H., Muro S., Imura H., Nakao K. Bacterial lipopolysaccharide-induced expression of interleukin-6 messenger ribonucleic acid in the rat hypothalamus, pituitary, adrenal gland, and spleen. Endocrinology. 1993 Dec;133(6):2574–2578. doi: 10.1210/endo.133.6.8243280. [DOI] [PubMed] [Google Scholar]
  39. Murdoch G. H., Potter E., Nicolaisen A. K., Evans R. M., Rosenfeld M. G. Epidermal growth factor rapidly stimulates prolactin gene transcription. Nature. 1982 Nov 11;300(5888):192–194. doi: 10.1038/300192a0. [DOI] [PubMed] [Google Scholar]
  40. Ohmichi M., Hirota K., Koike K., Kurachi H., Ohtsuka S., Matsuzaki N., Yamaguchi M., Miyake A., Tanizawa O. Binding sites for interleukin-6 in the anterior pituitary gland. Neuroendocrinology. 1992 Feb;55(2):199–203. doi: 10.1159/000126115. [DOI] [PubMed] [Google Scholar]
  41. Patterson P. H. The emerging neuropoietic cytokine family: first CDF/LIF, CNTF and IL-6; next ONC, MGF, GCSF? Curr Opin Neurobiol. 1992 Feb;2(1):94–97. doi: 10.1016/0959-4388(92)90169-l. [DOI] [PubMed] [Google Scholar]
  42. Rathjen P. D., Toth S., Willis A., Heath J. K., Smith A. G. Differentiation inhibiting activity is produced in matrix-associated and diffusible forms that are generated by alternate promoter usage. Cell. 1990 Sep 21;62(6):1105–1114. doi: 10.1016/0092-8674(90)90387-t. [DOI] [PubMed] [Google Scholar]
  43. Reichlin S. Neuroendocrine-immune interactions. N Engl J Med. 1993 Oct 21;329(17):1246–1253. doi: 10.1056/NEJM199310213291708. [DOI] [PubMed] [Google Scholar]
  44. Ritz J., Campen T. J., Schmidt R. E., Royer H. D., Hercend T., Hussey R. E., Reinherz E. L. Analysis of T-cell receptor gene rearrangement and expression in human natural killer clones. Science. 1985 Jun 28;228(4707):1540–1543. doi: 10.1126/science.2409597. [DOI] [PubMed] [Google Scholar]
  45. Rose T. M., Bruce A. G. Oncostatin M is a member of a cytokine family that includes leukemia-inhibitory factor, granulocyte colony-stimulating factor, and interleukin 6. Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8641–8645. doi: 10.1073/pnas.88.19.8641. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Rumpold H., Kraft D., Obexer G., Böck G., Gebhart W. A monoclonal antibody against a surface antigen shared by human large granular lymphocytes and granulocytes. J Immunol. 1982 Oct;129(4):1458–1464. [PubMed] [Google Scholar]
  47. Said J. W., Sassoon A. F., Shintaku I. P., Chien K., Pinkus G. S. Immuno-ultrastructural localization of B-cell-specific monoclonal antibodies B1 and B2. J Histochem Cytochem. 1986 May;34(5):607–611. doi: 10.1177/34.5.3517145. [DOI] [PubMed] [Google Scholar]
  48. Sherry S. H., Guay A. T., Lee A. K., Hedley Whyte E. T., Federman M., Freidberg S. R., Woolf P. D. Concurrent production of adrenocorticotropin and prolactin from two distinct cell lines in a single pituitary adenoma: a detailed immunohistochemical analysis. J Clin Endocrinol Metab. 1982 Nov;55(5):947–955. doi: 10.1210/jcem-55-5-947. [DOI] [PubMed] [Google Scholar]
  49. Smith A. G., Heath J. K., Donaldson D. D., Wong G. G., Moreau J., Stahl M., Rogers D. Inhibition of pluripotential embryonic stem cell differentiation by purified polypeptides. Nature. 1988 Dec 15;336(6200):688–690. doi: 10.1038/336688a0. [DOI] [PubMed] [Google Scholar]
  50. Spangelo B. L., Jarvis W. D., Judd A. M., MacLeod R. M. Induction of interleukin-6 release by interleukin-1 in rat anterior pituitary cells in vitro: evidence for an eicosanoid-dependent mechanism. Endocrinology. 1991 Dec;129(6):2886–2894. doi: 10.1210/endo-129-6-2886. [DOI] [PubMed] [Google Scholar]
  51. Stahl J., Gearing D. P., Willson T. A., Brown M. A., King J. A., Gough N. M. Structural organization of the genes for murine and human leukemia inhibitory factor. Evolutionary conservation of coding and non-coding regions. J Biol Chem. 1990 May 25;265(15):8833–8841. [PubMed] [Google Scholar]
  52. Stewart C. L., Kaspar P., Brunet L. J., Bhatt H., Gadi I., Köntgen F., Abbondanzo S. J. Blastocyst implantation depends on maternal expression of leukaemia inhibitory factor. Nature. 1992 Sep 3;359(6390):76–79. doi: 10.1038/359076a0. [DOI] [PubMed] [Google Scholar]
  53. Suda T., Tozawa F., Ushiyama T., Tomori N., Sumitomo T., Nakagami Y., Yamada M., Demura H., Shizume K. Effects of protein kinase-C-related adrenocorticotropin secretagogues and interleukin-1 on proopiomelanocortin gene expression in rat anterior pituitary cells. Endocrinology. 1989 Mar;124(3):1444–1449. doi: 10.1210/endo-124-3-1444. [DOI] [PubMed] [Google Scholar]
  54. Tomida M., Yamamoto-Yamaguchi Y., Hozumi M. Purification of a factor inducing differentiation of mouse myeloid leukemic M1 cells from conditioned medium of mouse fibroblast L929 cells. J Biol Chem. 1984 Sep 10;259(17):10978–10982. [PubMed] [Google Scholar]
  55. Tsagarakis S., Kontogeorgos G., Giannou P., Thalassinos N., Woolley J., Besser G. M., Grossman A. Interleukin-6, a growth promoting cytokine, is present in human pituitary adenomas: an immunocytochemical study. Clin Endocrinol (Oxf) 1992 Aug;37(2):163–167. doi: 10.1111/j.1365-2265.1992.tb02301.x. [DOI] [PubMed] [Google Scholar]
  56. Vankelecom H., Carmeliet P., Van Damme J., Billiau A., Denef C. Production of interleukin-6 by folliculo-stellate cells of the anterior pituitary gland in a histiotypic cell aggregate culture system. Neuroendocrinology. 1989 Jan;49(1):102–106. doi: 10.1159/000125097. [DOI] [PubMed] [Google Scholar]
  57. Velkeniers B., Vergani P., Trouillas J., D'Haens J., Hooghe R. J., Hooghe-Peters E. L. Expression of IL-6 mRNA in normal rat and human pituitaries and in human pituitary adenomas. J Histochem Cytochem. 1994 Jan;42(1):67–76. doi: 10.1177/42.1.8263325. [DOI] [PubMed] [Google Scholar]
  58. Voss J. W., Rosenfeld M. G. Anterior pituitary development: short tales from dwarf mice. Cell. 1992 Aug 21;70(4):527–530. doi: 10.1016/0092-8674(92)90422-9. [DOI] [PubMed] [Google Scholar]
  59. Waring P., Wycherley K., Cary D., Nicola N., Metcalf D. Leukemia inhibitory factor levels are elevated in septic shock and various inflammatory body fluids. J Clin Invest. 1992 Nov;90(5):2031–2037. doi: 10.1172/JCI116083. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Yamamori T., Fukada K., Aebersold R., Korsching S., Fann M. J., Patterson P. H. The cholinergic neuronal differentiation factor from heart cells is identical to leukemia inhibitory factor. Science. 1989 Dec 15;246(4936):1412–1416. doi: 10.1126/science.2512641. [DOI] [PubMed] [Google Scholar]
  61. Yamashita S., Melmed S. Insulinlike growth factor I regulation of growth hormone gene transcription in primary rat pituitary cells. J Clin Invest. 1987 Feb;79(2):449–452. doi: 10.1172/JCI112832. [DOI] [PMC free article] [PubMed] [Google Scholar]