The anterior pituitary can develop benign tumors of different sizes, classified as micro- and macroadenomas, frequently associated with high levels of hormone production, leading to different associated syndromes like Cushing’s disease, acromegaly or prolactinomas. Much work has been done in order to understand the signaling pathways and the factors and hormones involved in the pituitary tumorigenic process. In recent years, much evidence has been collected and it is now well documented that cytokines of the gp130 family, such as interleukin-6, that use gp130 as a common signaling protein stimulate not only the proliferation but also the hormone secretion of pituitary cells. Experiments in vivo have shown that the overexpression of the gp130 receptor resulted in pituitary abnormal growth. Moreover, it has been recently described that bone morphogenetic protein-4 (BMP-4), a member of the TGF-β family, has a stimulatory role on lactosomatotropic cells promoting the development of prolactinomas but it has an inhibitory action on the corticotropic lineage. This inhibitory action prevents Cushing’s disease progression. Furthermore, BMP-4 mediates the antiproliferative action of retinoic acid in these cells. The present review highlights the most recent work about gp130 and TGF-β cytokine families and their role in pituitary tumorigenesis.

Keywords:
gp130 family, TGF-β family, Pituitary action of cytokines
1.
Asa SL, Ezzat S: The pathogenesis of pituitary tumours. Nat Rev Cancer 2002;2:836–849.
2.
Kovacs K, Horvath E, Vidal S: Classification of pituitary adenomas. J Neurooncol 2001;54:121–127.
3.
Yu R, Melmed S: Oncogene activation in pituitary tumors. Brain Pathol 2001;11:328–341.
4.
Arzt E, Pereda MP, Castro CP, Pagotto U, Renner U, Stalla GK: Pathophysiological role of the cytokine network in the anterior pituitary gland. Front Neuroendocrinol 1999;20:71–95.
5.
Arzt E: gp130 cytokine signaling in the pituitary gland: a paradigm for cytokine-neuroendocrine pathways. J Clin Invest 2001;108:1729–1733.
6.
Hirano T: Interleukin-6; in Thomson AW (ed): The Cytokine Handbook, ed 2. Osaka, Academic Press, 1994, pp 145–168.
7.
Kishimoto T, Taga T, Akira S: Cytokine signal transduction. Cell 1994;76:253–262.
8.
Kishimoto T, Akira S, Narazaki M, Taga T: Interleukin-6 family of cytokines and gp130. Blood 1995;86:1243–1254.
9.
Heinrich PC, Behrmann I, Muller-Newen G, Schaper F, Graeve L: Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J 1998;334:297–314.
10.
Yoshida K, Taga T, Saito M, Suematsu S, Kumanogoh A, Tanaka T, Fujiwara H, Hirata M, Yamagami T, Nakahata T, Hirabayashi T, Yoneda Y, Tanaka K, Wang WZ, Mori C, Skiota K, Yoshida N, Kishimoto T: Targeted disruption of gp130, a common signal transducer for the interleukin-6 family, leads to myocardial and hematological disorders. Proc Natl Acad Sci USA 1996;93:407–411.
11.
Takeda K, Noguchi K, Shi W, Tanaka T, Matsumoto M, Yoshida N, Kishimoto T, Akira S: Targeted disruption of the mouse Stat3 gene leads to early embryonic lathality. Proc Natl Acad Sci USA 1997;94:3801–3804.
12.
Rodig SJ, Meraz MA, White JM, Lampe PA, Riley JK, Arthur CD, Kind KL, Sheehan KCF, Yin L, Pennica D, Johnson EM, Schreiber RD: Disruption of the JaK1 gene demonstrates obligatory and nonredundant roles of the JaKs in cytokine-induced biologic responses. Cell 1998;93:373–383.
13.
Betz UA, Bloch W, van den Broek M, Yoshida K, Taga T, Kishimoto T, Addicks K, Rajewsky K, Muller W: Postnatally induced inactivation of gp130 in mice results in neurological, cardiac, hematopoietic, immunological, hepatic, and pulmonary defects. J Exp Med 1998;188:1955–1965.
14.
Massague J: How cells read TGF-β signals. Nat Rev Mol Cell Biol 2000;1:169–178.
15.
Massague J: TGF-β signal transduction. Annu Rev Biochem 1998;67:753–791.
16.
Shi Y, Massague J: Mechanisms of TGF-β signaling from cell membrane to the nucleus. Cell 2003;113:685–700.
17.
Spangelo BL, MacLeod RM, Isakson PC: Production of interleukin-6 by anterior pituitary cells in vitro. Endocrinology 1990;126:582–586.
18.
Vankelecom H, Carmeliet P, Van Damme J, Billiau A, Denef C: Production of interleukin-6 by folliculostellate cells of the anterior pituitary gland in a histiotypic cell aggregate culture system. Neuroendocrinology 1989;49:102–106.
19.
Ray D, Melmed S: Pituitary cytokine and growth factor expression and action. Endocr Rev 1997;18:206–228.
20.
Arzt E, Páez Pereda M, Costas M, Sauer J, Renner U, Holsboer F, Stalla GK: Cytokine expression and molecular mechanisms of their auto/paracrine regulation of anterior pituitary function and growth. Ann NY Acad Sci 1998;840:525–531.
21.
Renner U, Gloddek J, Páez Pereda M, Arzt E, Stalla GK: Regulation and role of intrapituitary IL-6 production by folliculostellate cells. Domest Anim Endocrinol 1998;15:353–362.
22.
Arzt E, Páez Pereda M, Perez Castro C, Kovalovsky D, Nagashima AC, Renner U, Stalla GK: Cytokines and pituitary function; in Beck-Peccoz P (ed): Regulation in Pituitary Hormone Secretion. BioScientifica Ltd. Bristol, UK. 1999, pp 15–26.
23.
Spangelo BL, Gorospe WC: Role of the cytokines in the neuroendocrine-immune system axis. Front Neuroendocrinol 1995;16:1–12.
24.
Páez Pereda M, Lohrer P, Kovalovsky D, Perez Castro C, Goldberg V, Losa M, Chervín A, Berner S, Molina H, Stalla GK, Arzt E: Interleukin-6 is inhibited by glucocorticoids and stimulates ACTH secretion and POMC expression in human corticotroph pituitary adenomas. Exp Clin Endocrinol Diabetes 2000;108:202–207.
25.
Scully KM, Rosenfeld MG: Pituitary development: regulatory codes in mammalian organogenesis. Science 2002;295:2231–2235.
26.
Treier M, Gleiberman AS, O’Connell SM, Szeto DP, McMahon JA, McMahon AP, Rosenfeld MG: Multistep signaling requirements for pituitary organogenesis in vivo. Genes Dev 1998;12:1691–1704.
27.
Drouin J: Molecular mechanisms of pituitary differentiation and regulation: implications for hormone deficiencies and hormone resistance syndromes. Front Horm Res 2006;35:74–87.
28.
Dasen JS, Rosenfeld MG: Signaling and transcriptional mechanisms in pituitary development. Annu Rev Neurosci 2001;24:327–355.
29.
Ericson J, Norlin S, Jessell TM, Edlund T: Integrated FGF and BMP signaling controls the progression of progenitor cell differentiation and the emergence of pattern in the embryonic anterior pituitary. Development 1998;125:1005–1015.
30.
Watkins-Chow DE, Camper SA: How many homeobox genes does it take to make a pituitary gland? Trends Genet 1998;14:284–290.
31.
Páez-Pereda M, Giacomini D, Refojo D, Nagashima AC, Hopfner U, Grubler Y, Chervin A, Goldberg V, Goya R, Hentges ST, Low MJ, Holsboer F, Stalla GK, Arzt E: Involvement of bone morphogenetic protein-4 in pituitary prolactinoma pathogenesis through a Smad/estrogen receptor crosstalk. Proc Natl Acad Sci USA 2003;100:1034–1039.
32.
Giacomini D, Páez-Pereda M, Theodoropoulou M, Labeur M, Refojo D, Gerez J, Chervin A, Berner S, Losa M, Buchfelder M, Renner U, Stalla GK, Arzt E: Bone morphogenetic protein-4 inhibits corticotroph tumor cells: involvement in the retinoic acid inhibitory action. Endocrinology 2006;147:247–256.
33.
Takeda M, Otsuka F, Suzuki J, Kishida M, Ogura T, Tamiya T, Makino H: Involvement of activin/BMP system in development of human pituitary gonadotropinomas and nonfunctioning adenomas. Biochem Biophys Res Commun 2003;306:812–818.
34.
Lyson K, McCann SM: The effect of interleukin-6 on pituitary hormone release in vivo and in vitro. Neuroendocrinology 1991;54:262–266.
35.
Arzt E, Buric R, Stelzer G, Stalla J, Sauer J, Renner U, Stalla GK: Interleukin (IL) involvement in anterior pituitary cell growth regulation: effects of IL-2 and IL-6. Endocrinology 1993;132:459–467.
36.
Renner U, Gloddek J, Arzt E, Inoue K, Stalla GK: Interleukin-6 is an autocrine growth factor for folliculostellate-like TtT/GF mouse pituitary tumor cells. Exp Clin Endocrinol Diabetes 1997;105:345–352.
37.
Sawada T, Koike K, Kanda Y, Ikegami H, Jikihara T, Maeda T, Osako Y, Hirota K, Miyake A: Interleukin-6 stimulates cell proliferation of rat anterior pituitary clonal cell lines in vitro. J Endocrinol Invest 1995;18:83–90.
38.
Páez Pereda M, Goldberg V, Chervin A, Carrizo G, Molina A, Andrada J, Sauer J, Renner U, Stalla GK, Arzt E: Interleukin (IL)-2 and IL-6 regulate c-fos protooncogene expression in human pituitary adenoma explants. Mol Cell Endocrinol 1996;124:33–42.
39.
Perez Castro C, Nagashima AC, Pereda MP, Goldberg V, Chervin A, Largen P, Renner U, Stalla GK, Arzt E: The gp130 cytokines interleukin-11 and ciliary neurotropic factor regulate through specific receptors the function and growth of lactosomatotropic and folliculostellate pituitary cell lines. Endocrinology 2000;141:1746–1753.
40.
Nudi M, Ouimette JF, Drouin J: Bone morphogenic protein (Smad)-mediated repression of proopiomelanocortin transcription by interference with Pitx/Tpit activity. Mol Endocrinol 2005;19:1329–1342.
41.
Páez-Pereda M, Kovalovsky D, Hopfner U, Theodoropoulou M, Pagotto U, Uhl E, Losa M, Stalla J, Grubler Y, Missale C, Arzt E, Stalla G: Retinoic acid prevents experimental Cushing syndrome. J Clin Invest 2001;108:1123–1131.
42.
Castillo V, Giacomini D, Páez-Pereda M, Stalla J, Labeur M, Theodoropoulou M, Holsboer F, Grossman AB, Stalla GK, Arzt E: Retinoic acid as a novel medical therapy for Cushing’s disease in dogs. Endocrinology 2006;147:4438–4444.
43.
Horiguchi A, Oya M, Marumo K, Murai M: STAT3, but not ERKs, mediates the IL-6-induced proliferation of renal cancer cells, ACHN and 769P. Kidney Int 2002;61:926–938.
44.
Liu XH, Kirschenbaum A, Lu M, Yao S, Klausner A, Preston C, Holland JF, Levine AC: Prostaglandin E2 stimulates prostatic intraepithelial neoplasia cell growth through activation of the interleukin-6/GP130/STAT-3 signaling pathway. Biochem Biophys Res Commun 2002;290:249–255.
45.
Campbell CL, Jiang Z, Savarese DM, Savarese TM: Increased expression of the interleukin-11 receptor and evidence of STAT3 activation in prostate carcinoma. Am J Pathol 2001;158:25–32.
46.
Burger R, Guenther A, Bakker F, Schmalzing M, Bernand S, Baum W, Duerr B, Hocke GM, Steininger H, Gebhart E, Gramatzki M: gp130 and ras mediated signaling in human plasma cell line INA-6: a cytokine-regulated tumor model for plasmacytoma. Hematol J 2001;2:42–53.
47.
Leung CKH, Shiu PC: Required presence of both estrogen and pituitary factors for the growth of human breast cancer cells in athymic nude mice. Cancer Res 1981;41:546–551.
48.
Yano T, Uozumi T, Kawamoto K, Mukada K, Onda J, Ito A, Fujimoto N: Photodynamic therapy for rat pituitary tumor in vitro and in vivo using pheophorbide-a and white light. Lasers Surg Med 1991;11:174–182.
49.
Davalli AM, Galbiati F, Bertuzzi F, Polastri L, Pontiroli AE, Perego L, Freschi M, Pozza G, Folli F, Meoni C: Insulin-secreting pituitary GH3 cells: a potential β-cell surrogate for diabetes cell therapy. Cell Transplant 2000;9:841–851.
50.
Castro CP, Giacomini D, Nagashima AC, Onofri C, Graciarena M, Kobayashi K, Páez-Pereda M, Renner U, Stalla GK, Arzt E: Reduced expression of the cytokine transducer gp130 inhibits hormone secretion, cell growth, and tumor development of pituitary lactosomatotrophic GH3 cells. Endocrinology 2003;144:693–700.
51.
Tone E, Kunisawa K, Kumanogoh A, Negoro S, Funamoto M, Osugi T, Kishimoto T, Yamauchi-Takihara K: gp130-dependent signalling pathway is not enhanced in gp130 transgenic heart after LIF stimulation. Cytokine 2000;12:1512–1518.
52.
Koyama C, Matsumoto H, Sakai T, Wakabayashi K, Ito A, Couch EF, Inoue K: Pituitary folliculo-stellate-like cells stimulate somatotropic pituitary tumor growth in nude mice. Endocr Pathol 1995;6:67–75.
53.
Graciarena M, Carbia-Nagashima A, Onofri C, Perez-Castro C, Giacomini D, Renner U, Stalla GK, Arzt E: Involvement of the gp130 cytokine transducer in MtT/S pituitary somatotroph tumour development in an autocrine-paracrine model. Eur J Endocrinol 2004;151:595–604.
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