Pathophysiological Role of the Cytokine Network in the Anterior Pituitary Gland

Frontiers in Neuroendocrinology 20, 71–95 (1999)Article ID frne.1998.0176, available online at http://www.idealibrary.com on

Pathophysiological Role of the Cytokine Networkin the Anterior Pituitary Gland

Eduardo Arzt,*,1 Marcelo Paez Pereda,† Carolina Perez Castro,*Uberto Pagotto,† Ulrich Renner,† and Gunter K. Stalla†

*Laboratorio de Fisiologıa y Biologıa Molecular. Dept. de Biologıa, FCEN, Universidadde Buenos Aires, Buenos Aires, Argentina; and †Department of Endocrinology,

Max-Planck Institute of Psychiatry, Kraepelinstrasse 10, 80804 Munich, Germany

Recent evidence has demonstrated that cytokines and other growth factors act in theanterior pituitary gland. Using the traditional criteria employed to determine autocrineor paracrine functions our review shows that, in addition to their role as lymphocytemessengers, certain cytokines are autocrine or paracrine regulators of anterior pituitaryfunction and growth. The cytokines known to regulate and/or be expressed in the anteriorpituitary include the inflammatory cytokine family (IL-1 and its endogenous antagonist,IL-1ra; TNF-a, and IL-6), the Th1-cytokines (IL-2 and IFN-g), and other cytokines suchas LIF, MIF, and TGF-b. This review examines at the cellular, molecular, and physiologi-cal levels whether: (1) each cytokine alters some aspect of pituitary physiology; (2)receptors for the cytokine are expressed in the gland; and (3) the cytokine is produced inthe anterior pituitary. Should physiological stimuli regulate pituitary cytokine produc-tion, this would constitute additional proof of their autocrine/paracrine role. In thiscontext, we analyze in this review the current literature on the actions of cytokinesknown to regulate anterior pituitary hormone secretion, selecting the in vivo studies thatsupport the direct action of the cytokine in the anterior pituitary. Further support fordirect regulatory action is provided by in vitro studies, in explant cultures or pituitary celllines. The cytokine receptors that have been demonstrated in the pituitary of severalspecies are also discussed. The endogenous production of the homologous cytokines andthe regulation of this expression are analyzed. The evidence indicating that cytokinesalso regulate the growth and proliferation of pituitary cells is reviewed. This action isparticularly important since it suggests that intrinsically produced cytokines may play arole in the pathogenesis of pituitary adenomas. The complex cell to cell communicationinvolved in the action of these factors is discussed. KEY WORDS: cytokines; anteriorpituitary; adenoma growth; autocrine/paracrine. r 1999 Academic Press

CLASSIFICATION, FUNCTION, AND SOURCES OF THE CYTOKINES THAT AREEXPRESSED AND/OR ACT IN THE PITUITARY GLAND

Cytokine is a generic term for a family of proteins originally described, on thebasis of their biological activity, in the immune system. It is a synonym for other

Address correspondence and reprint requests to Prof. Dr. E. Arzt, Lab. Fisiologıa y Biologıa Molecular,Dept. de Biologıa, FCEN, Universidad de Buenos Aires, Ciudad Universitaria, Pabellon II, 1428 BuenosAires, Argentina. Fax: 54-1-5763321; and Prof. Dr. G.K. Stalla, Max-Planck Institute of Psychiatry,
Department of Endocrinology, Kraepelinstr. 10, 80804 Munich, Germany. Fax: 49-89-306 22 605.
1 Member of the Argentine National Research Council (CONICET) and recipient of a fellowshipof the John Simon Guggenheim Memorial Foundation.

71 0091-3022/99 $30.00Copyright r 1999 by Academic Press

All rights of reproduction in any form reserved.

frne0176@xyserv2/disk3/CLS jrnl/GRP frne/JOB frne20-1/DIV 149a02 rich

terms used, such as lymphokines, monokines, and interleukins. The termcytokines, in fact, is used to denote that they are also produced by nonlymphoidcells. Currently, the cloned cytokines include 17 interleukins (numbered assuch) as well as a number of other cytokines which retain their activity-basednames, e.g., TNF-a2 and IFN-g. Cytokines are proteins or glycoproteins en-coded by genes for which there is only one copy per haploid cell. They aresegmented, being composed of several exons. They have low molecular weight,around 15–30 kDa. In humans a number of cytokine genes are located onchromosome 5 and TNF-a is closely associated with lymphotoxin in chromo-some 6. The common location raises the possibility that they may be under theinfluence of common regulatory elements. They are usually produced by cells inresponse to induction signals generated from the cell surface and they seem tobe controlled particularly at the level of transcription.

Cytokines may not only be produced by different cells but also act on multiplecell types, a characteristic that makes them pleiotropic. Moreover, in manycases their actions are redundant. Another general property is that they mayact, in paracrine or autocrine pathways, on the same cells in which they areproduced.

Both the ligands and their receptors are classified into several families.There are four big families of receptors. Type I are characterized by conservedfour-cysteine residues in the N-termini and a tryptophan–serine–X–tryptophan–serine (WSXWS) motif just above the transmembrane portions. To this familybelong the receptors for IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, GM-CSF, and G-CSF.Interestingly, GH and PRL receptors also belong to this family. Type II aredifferent types of interferon receptors. Type III are homologous to the proteinFas and the nerve growth factor receptor and include the TNF receptors (p55and p75). Type IV belong to the superfamily of immunoglobulins, with severalextracellular domains homologous to immunoglobulins. This family includesthe IL-1 receptors (Types I and II).

The ligands can also be organized in several groups: (1) Mediators of inflam-mation, including IL-1, TNF-a, and IL-6, or antiinflammatory cytokines, suchas IL-1ra and TGF-b. (2) Markers of Th1 lymphocyte activation and prolifera-

2 Abbreviations used: adrenocorticotropic hormone, ACTH; bacterial endotoxin, lipopolysaccha-ride, LPS; corticotrophin releasing hormone, CRH; epidermal growth factor, EGF; fibroblastgrowth factor, FGF; follicle stimulating hormone, FSH; folliculostellate cells, FS cells; hypothalamic–pituitary–adrenal axis, HPA axis; insulin-like growth factors, IGF-I and IGF-II; interferon-gamma,IFN-g; interleukin, IL; interleukin-receptor, IL-R; interleukin-1 receptor antagonist, IL-1ra; gluco-corticoid increasing factor, GIF; granulocyte-macrophage colony stimulating factor, GM-CSF;granulocyte stimulating factor, G-CSF; knockout, KO; leukemia inhibitory factor, LIF; luteinizinghormone, LH; macrophage-migration inhibitory factor, MIF; nerve growth factor, NGF; phorbolesters, PMA; pituitary adenylate cyclase activating polypeptide, PACAP; platelet-derived growthfactor, PDGF; proopiomelanocortin, POMC; T helper, Th; thyrotropin, TSH; thyrotropin releasing

72 ARZT ET AL.

hormone, TRH; transforming growth factor-a, TGF-a; transforming growth factor-b, TGF-b; tumornecrosis factor-a, TNF-a; vascular endothelial growth factor, VEGF; vasoactive intestinal polypep-tide, VIP.


tion, including IL-2 and IFN-g, but also LIF and TNF-a. (3) Markers of Th2lymphocyte activation, proliferation, and function, such as IL-4, IL-5, IL-10,and IL-13. (4) Regulators of the efferent phase of the immune response,including IL-5, IL-10, and IL-12. (5) Stimulators of the hematopoietic cellprogenitors, including IL-3, IL-7, GM-CSF and M-CSF.

All types of receptors are expressed in the different cells of the anteriorpituitary gland, but so far only cytokines from groups 1 and 2 have beendescribed as autocrine/paracrine factors in this gland.

Inflammatory Cytokine Family: IL-1 and Its Endogenous Antagonist IL-1ra,TNF-a, and IL-6

IL-1 plays an important role in responsiveness to infection and is involved inmany other biological processes (47). It is produced mainly by activated mono-cytes and macrophages. IL-1a and IL-1b bind to IL-1 receptor Types I and IIand share most of their biological activities (47, 116). Monocytes expressIL-1RII (41, 104). IL-1ra, found in monocyte supernatants (8), has been cloned(50). It shares homologous sequences with IL-1 and binds to the same receptors(50, 63, 125). IL-1ra antagonizes IL-1 activity without producing any agonisticeffects (63). IL-1RII also acts as an IL-1 antagonist (41). LPS induces IL-1 andIL-1ra synthesis in the same monocyte (7, 9, 125). However, they may bedifferentially regulated (9, 125).

In the immune system, IL-6 is mainly produced by monocytes/macrophagesand activated T cells. It shares many biological actions with IL-1, both beingresponsible for the acute phase and inflammatory response. It also induces thedifferentiation of B cells and proliferation of malignant plasmocytes. IL-6 actsvia the IL-6 receptor, which uses gp130 protein as an initial cellular signaltransducer without activating tyrosine kinases (83).

TNF-a is a pleiotropic cytokine capable of killing mammalian cells in vitroand in vivo through a number of cellular effects, including cytotoxicity/apoptosis (17, 27, 31, 40, 108, 154). The shock and tissue injury that occur inresponse to bacterial endotoxin are largely mediated by IL-1 and TNF-a, whichcan also mediate cellular injury in normal tissues (27–29, 115, 158, 163). Thereduction of the side effects of these cytokines is a major goal in the successfulclinical management of endotoxemia.

Th1 Cytokines: IL-2 and IFN-g

Two types of T helper lymphocytes, Th1 and Th2, that are responsible for thecollaboration with T and B cell responses, respectively, are characterizeddepending on the cytokines they produce. Th1 cells produce IL-2 and IFN-g,

73CYTOKINE ROLE IN THE PITUITARY

while Th2 cells produce, IL-4, IL-5, IL-10, and IL-13. A balance between theactivation of Th1 and Th2 responses has been described. Factors from Th1 cellsinhibit Th2 response and vice versa (14, 48, 74, 117). The Th1 cytokine IFN-g


has been described as activating the cellular response mainly through activa-tion of macrophages, which in turn start to produce a number of proinflamma-tory cytokines, among them IL-1 (62, 75, 86), and to restore monocyte deactiva-tion in septic patients. On the contrary, the Th2 cytokine IL-4 has been found toinhibit the cellular response by different mechanisms, including the inhibitionof IL-1 and other cytokines. Apart from their different functions, IFN-g andIL-4 are regulated differently by glucocorticoids; while glucocorticoids inhibitthe production of IFN-g (177), they stimulate the production of IL-4 (126),promoting a Th2 cytokine response (126).

IL-2 is produced by activated T helper cells. The clonal expansion of the Thelper cells that produce IL-2 and other T cells is critically dependent on thegeneration of IL-2 and IL-2 receptors; thus, IL-2 constitutes an auto/paracrinesignal for T cell proliferation. IL-2 interacts with cells binding to a receptor ofwhich there are different forms with differing affinities for IL-2. A high-affinityreceptor mediates the physiological response to IL-2. The receptor is composedof three subunits, a or p55, b or p75, and g, the high-affinity receptor resultingfrom the trimer abg combination (91, 153).

Other Cytokines: LIF, MIF, and TGF-b

LIF is a cytokine produced by monocytes/macrophages and T cells, originallydescribed as a factor inducing differentiation and suppressing proliferation of amonocytic leukemia cell line. It is not only involved in hematopoesis but alsoexhibits numerous other biological effects, sharing many of the biologicalactivities of IL-6. MIF is a product of activated T lymphocytes that inhibitsmonocyte/macrophage migration; it was one of the first cytokines discoveredbut was cloned in the middle of the 1980s. Additional studies identified themacrophage to be an additional source of MIF in vivo.

TGF-b is a member of a diverse protein family (TGF-b gene family, includingTGF-b 1 to 5, activin, inhibin, and follistatin) which exhibits multiple biologicalactivities in many different tissues (133). In the immune system it is producedby monocytes/macrophages and lymphocytes. Its major functions involve theactivation of the isotype switch in B cells for IgA production and the inhibitionof the IL-1 system: TGF-b1 inhibits IL-1 production in response to LPS andinduces IL-1ra synthesis (161).

THE CONCEPT OF AUTOCRINE AND/OR PARACRINE FUNCTION:REQUIREMENTS FOR FUNCTIONAL CLASSIFICATION. THE IMPORTANCE

OF CELL-TO-CELL COMMUNICATION IN THE ANTERIOR PITUITARY GLAND

Tissue architecture is of pivotal importance in the functioning of the anterior

74 ARZT ET AL.

pituitary gland. In recent years an increasing number of reports suggest thatthe regulation within the gland comes from local interactions among pituitarycells and their intercellular environments (122). This regulation occurs through


autocrine, paracrine, and cell/extracellular matrix interactions. Functionalcommunication between different pituitary cell types is important in paracrineinteractions affecting hormone secretion (13). FS cells have been proposed toplay an essential role in the organization of paracrine communication innormal tissue (6). Several factors participate in these pathways. We postulatethat, according to the evidence and contributions in the last 10 years, amongthem, cytokines play an important role. Cytokines, in addition to their role aslymphocyte messengers, also are expressed in the pituitary gland and wepropose that they act as paracrine or autocrine regulators at the anteriorpituitary, where they regulate hormone secretion and pituitary growth andhave a physiopathological role in the maintenance of anterior pituitary homeo-stasis. We will consider the following criteria in establishing an autocrine orparacrine role for a cytokine at the level of the anterior pituitary: (1) Thecytokine has an effect on the pituitary that alters some aspect of pituitaryphysiology; (2) the cytokine is produced in the anterior pituitary; (3) receptorsfor the cytokine are expressed in the pituitary; (4) should physiological stimulialter pituitary cytokine production, this would constitute additional proof oftheir autocrine/paracrine role. Functional assays should be used to demon-strate a putative intrapituitary role for these peptides.

CYTOKINE DIRECT REGULATORY ACTION ON PITUITARY FUNCTION

In Vivo Studies

Studies in Animal Models

The stimulatory action of soluble factors produced by the immune system,namely, GIF, and particularly IL-1 was first described by Besedovsky et al.(24–26). The effects of this and other cytokines have been extensively studied.IL-1 is the most potent cytokine showing GIF activity. Despite some discrepan-cies in the literature (95), it appears to act at all levels of the HPA axis,stimulating the secretion of CRH, ACTH, and glucocorticoids (18, 23, 73). Inthis context, many studies have been performed showing the action of cyto-kines, in vivo in animal models, in the regulation of plasma levels of pituitaryhormones. We will not address this issue, since it is reviewed in depth else-where (23). We will only remark on some studies that support the notion that,in vivo, the specific cytokine may be acting directly on the anterior pituitary.

In rats, it has been shown that CRH can sensitize the pituitary gland to thedirect ACTH releasing activity of IL-1 (121). IL-6 stimulates the release ofACTH in normal rats (110). Suboptimal amounts of IL-1a and IL-6 synergize toinduce an early (30–60 min) ACTH response in mice (123). In agreement withthis synergism, it has been shown that an anti-IL-6 antibody blocked the


IL-1-induced increase in plasma ACTH in mice (112). A single intraperitonealinjection of IL-1b in rats induces an increase in POMC mRNA in the pituitary,while IL-6 did not change POMC mRNA levels. Both IL-1b and IL-6 induced an


increase in ACTH levels at 4 h postinjection (70). Chronic infusion of IL-1resulted in a persistent elevation in ACTH levels in rats (150). This in vivotreatment induced an increase in spontaneous in vitro secretion of b-endor-phin, while the in vitro responses of the pituitary to CRH of animals treated invivo with IL-1 were diminished (150).

IL-2 injection also stimulates POMC gene expression in the pituitary of ratswithout concomitant changes in CRH gene expression in the hypothalamus,suggesting a direct effect on the pituitary (69). Treatment with IL-2 of normalrats or rats bearing pituitary allografts also increases plasma ACTH andb-endorphin, respectively (109, 178). One study noted that rat IL-2 stimulatedACTH release in the rat, while human IL-2 had no such activity (109). Thissuggests that some of the disparate findings in the literature, particularlythose studies failing to find ACTH-releasing activities of IL-2, may be due tospecies specificity effects.

In LIF gene KO mice a defect in the activation of the HPA axis was observed(3). ACTH levels are diminished after fasting in the KO animals and replace-ment of LIF restores the HPA response (3). Intravenous injection of TNF-aelevates ACTH in the rat with an unknown site of action (20, 139) andcerebroventricular administration of TNF-a produced a dose-dependent in-crease in plasma ACTH concentration (160).

Studies in Humans

In contrast to the large number of studies performed in animal models or invitro, only a few studies have been performed in humans. However, theavailable data validate in humans the actions found in the different experimen-tal models.

IL-1b stimulates the secretion of ACTH from pituitary cell cultures derivedfrom humans with Cushing’s disease (98). When IL-2 is administered to cancerpatients, plasma b-endorphin, ACTH, and cortisol levels increase (45, 92).Interferon-g has also been shown to stimulate ACTH release from pituitary cellcultures derived from patients with Cushing’s disease (98). Recombinant IL-6has been shown to activate the HPA axis in humans; at different doses IL-6treatment of cancer patients induces an increase in both ACTH and cortisolplasma levels (100, 101, 148).

In Vitro Studies

Primary Pituitary Cultures and Explants

The available evidence in vitro indicates that IL-1 acts at the level of the

76 ARZT ET AL.

pituitary, although the exact nature of this mechanism appears to depend onthe precise experimental model. In nearly identical studies utilizing pituitarymonolayer cultures, the secretion of GH, PRL, LH, and FSH has been reported


not to be influenced by IL-1b (162), whereas in the other study IL-1b stimulatedthe secretion of GH, LH, and TSH and inhibited the secretion of PRL (22). Thesecretion of PRL by normal rat pituitary cultures was also reported to beinhibited by IL-1b (57). Bernton et al. (22) and Keher et al. (82) found IL-1b tobe a potent stimulator of ACTH secretion. Uehara, however, found only a weakstimulation of ACTH secretion by IL-1b (162). IL-1b has also been reported toincrease ACTH secretion from perifused pituitary cells in a dose-dependentmanner (19, 35) as well as to have no effect on ACTH secretion (120). A nitricoxide synthase inhibitor did not affect IL-1-induced ACTH release in pituitaryrat cell cultures (72). The conclusion we draw from these studies is that whilethe literature is not completely consistent, the prevalent opinion is that IL-1stimulates the secretion of most hormones of the anterior pituitary directly.The exception is PRL, whose secretion appears to be inhibited by IL-1 (Table 1).

Picomolar concentrations of IL-6 stimulate the release of PRL, GH, and LHfrom dispersed cell cultures of normal rat pituitary cells, without alterations incAMP or inositol phosphates (143). IL-6 also enhances ACTH and GH releasefrom rat hemipituitary glands (96). Yamaguchi et al. confirmed that IL-6stimulates the release of PRL and LH from rat pituitary cells and demon-strated a stimulation of FSH release (175). In contrast to these stimulatoryeffects, pretreatment of anterior pituitary cells with IL-6 inhibits both forsko-lin- and VIP-stimulated activation of adenylate cyclase as well as inhibitingTRH-stimulated increases in inositol phosphate turnover and intracellularcalcium levels. However, IL-6 had no effect on basal levels of these intracellularsecond messengers (65). The basal release of PRL is inhibited by a polyclonalantiserum to rat IL-6, a functional test showing the involvement of intrinsicIL-6 in PRL production (147).

IL-2 has been shown to induce the release of ACTH by normal rat pituitary

TABLE 1

Summary of Studies About Action of Cytokines on Basal Hormone Releasein Vitro in Pituitary Cultures

ACTH

PRL LH GH TSH FSHNormal

(N)

CellLine(C)

Ade-noma

(A) N C A N C A N C A N C A N C A

IL-1 > > > </2 2 NR >/2 2 NR >/2 2 NR >/2 NR NR NR NR NRIL-2 > > NR > 2 NR < NR NR </2 > NR > NR NR < NR NRIL-6 > > NR > > NR > NR NR > > NR NR NR NR > NR NRLIF > > NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NRMIF NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NRTGF-b NR NR NR < < NR NR NR NR NR NR NR NR NR NR > NR NRTNF-a > > NR >/2 NR NR NR NR NR > NR NR >< NR NR NR NR NRIFN-g < NR > >< NR NR NR NR NR < NR NR NR NR NR NR NR NR


Note. NR, not reported; (2) no action; (>) stimulation; (<) inhibition; (><) stimulation andinhibition.


cells (55, 80, 140). Picomolar concentrations of IL-2 have been shown to alterthe secretion of PRL, LH, FSH, GH, and TSH in addition to ACTH (80, 81). IL-2enhances basal ACTH, PRL, and TSH and inhibits LH, FSH, and, at 1 h, GHrelease from rat hemipituitaries (80, 81). The IL-2 induced stimulation of PRLrelease can be blocked by dopamine (81). Thus IL-2 is unique among thecytokines in that the pattern of pituitary hormone secretion in response to IL-2is similar to that induced by stress (80).

TNF-a has been shown to have direct effects at anterior pituitary cells inculture. It blunts the release of ACTH and other pituitary hormones in re-sponse to hypothalamic factors (60). However, TNF-a treatment of hemipituitar-ies results in a dose-related increase in ACTH, GH, and TSH secretion, whilePRL secretion is not affected (105). Other authors have reported a stimulationof PRL release from dispersed anterior pituitary cells (87,88). In ovine pituitarycells TNF-a enhances the expression of GH mRNA (111). In cultured ratanterior pituitary cells, chronic treatment suppressed basal and GHRH-stimulated GH release, basal and TRH-induced PRL, and basal TSH, while itenhanced the maximal TSH response to TRH (71).

In mouse pituitary primary cell culture, LIF stimulates ACTH secretion(149).

Rat anterior pituitary cultures respond to IFN-g with reduced secretion ofACTH, GH, and PRL (167), an action that is mediated by FS cells (166). IFN-gas well as interferons a and b stimulate PRL release in primary rat pituitarycultures and this effect is believed to be mediated through IL-6 (174).

In rat pituitary cell cultures, TGF-b inhibits secretion of PRL (107) andstimulates FSH release (176). No data are yet available concerning a directaction of MIF on pituitary cells.

Several of the inconsistent findings across cell culture models discussed inthis section (Table 1), as well of those concerning the species effects of cytokines,illustrate the importance of the experimental model and in particular theexistence of cell–cell interaction in those models.

Anterior Pituitary Cell Lines

Despite the tumoral origin of AtT-20 cells, the studies performed on thismouse corticotrophic cell line are in agreement with those performed on thenormal rat pituitary cells (Table 1).

IL-1b stimulates the release of b-endorphin (52–54) and ACTH (58, 173) fromAtT-20 cells, apparently by way of the protein kinase A pathway (66). IL-1stimulates the increased glucocorticoid-induced transcriptional activity of theglucocorticoid receptor (GR) via the glucocorticoid response elements (GRE) inthese cells, suggesting that cytokines may modulate the sensitivity to glucocor-ticoid feedback (43). IL-6 stimulates the release of ACTH from AtT-20 cells (58).

78 ARZT ET AL.

IL-2 has been shown to increase the expression of POMC message (33) and toinduce the release of ACTH by AtT-20 cells (55, 140). LIF stimulates thesecretion of ACTH and the expression of POMC message in AtT-20 cells (4, 172).


In addition, in these cells, LIF potentiates the stimulatory action of CRH onACTH secretion (128). Also, oncostatin M (related to LIF) stimulates ACTH inthese cells (128). TNF-a stimulates ACTH synthesis in AtT-20 cells (84).

A few studies have been performed in somatomammotrophic tumoral celllines. In GH4 cells TGF-b suppresses both PRL synthesis and secretion (127).Both IL-2 and IL-6 stimulated GH release from GH3 cells, while only IL-6stimulated PRL release from these cells (10). Neither IL-1a or b affected GH orPRL release in GH3 somatomammotrophic cells (131). Additional experimentsin other anterior pituitary cell lines are necessary to provide further insights onthe mechanisms mediating the direct action of cytokines in the anteriorpituitary gland.

CYTOKINE RECEPTOR EXPRESSION IN THE ANTERIOR PITUITARY GLAND

IL-1R (quantitative autoradiography, binding assays, immunocytochemis-try) and IL-1R mRNA (RT–PCR) have been characterized in normal mouseanterior pituitary cells and in the corticotrophic tumor cell line AtT-20 (16, 32,46, 68, 119). In AtT-20 cells CRH induces an increase in the density of IL-1Rwithout altering their affinity (171). A single type of specific high-affinity IL-1R,whose density was not altered by treatment with LPS, was described in themouse using quantitative autoradiography (68). The expression of IL-1R in thisspecies was studied using competitive binding assays (152) and in situ localiza-tion, and there was a dense IL-1R binding distributed homogeneously over theanterior lobe (44). This binding increased after treatment with glucocorticoidsfor 7 days (15). It appears that both IL-1a and IL-1b act through a commonreceptor in the anterior pituitary (68, 103, 152). A high density of binding siteswas observed, using radiolabeled recombinant IL-1b, in the anterior pituitary,suggesting that these cells are direct targets of IL-1 action (99).

For IL-6, in contrast to the multiple studies about this cytokine expression inpituitary cells, only one study shows that IL-6 receptors are expressed in ratanterior pituitary cells (114).

IL-2R are expressed in AtT-20 cells and human corticotrophic adenoma cells(12). Both IL-2Ra chain mRNA and the corresponding membrane protein areexpressed in these cells (12). The expression of IL-2R is not restricted tocorticotrophic cells and has also been found in the GH3 somatomammotrophiccell line (10). IL-2R was also detected in human pituitary adenomas in cultureusing RT–PCR (136). IL-2Ra chain is also expressed in cultures of normal ratpituitary (11) and a related protein has been detected by affinity chromatogra-phy in AtT-20 and normal rat pituitary cultures (140). The relative incidence ofIL-2R colocalization with various pituitary hormone-producing cells in normalrats pituitaries is PRL ... ACTH .. GH . TSH 5 FSH 5 LH (11).Overnight preincubation of pituitary cells with IL-2 enhances the IL-2R num-


ber and dexamethasone co-incubation attenuates this upregulation by IL-2(157). Also, the b subunit of the receptor has been detected and cloned fromAtT-20 cells (124).


LIF binding sites have been demonstrated in developing human fetal pitu-itary and in normal and adenomatous adult human tissue (4). LIF receptormRNA was also demonstrated in pituitary cells by RT–PCR and is induced,in vivo, by LPS (170). Specific LIF binding sites are present in murine AtT-20cells (4).

Due to its action on PRL and FSH secretion, TGF-b receptors should beexpressed on lactotropes and gonadotropes. However, this has not yet beenstudied; TGF-b binding sites have been described only in GH3 cells (39).

In concert with its action on hormone secretion, receptors for TNF haverecently been described on pituitary cells. Both p55 and p75 mRNA areexpressed on AtT-20 corticotrophs and p55 mRNA in a pituitary FS cell line(TtT/GF) and a single type of binding site is present in both cell lines (84).

CYTOKINE EXPRESSION IN THE ANTERIOR PITUITARY

Endogenous production of IL-1 by anterior pituitary has been demonstrated(see Table 2 for summary of this and other cytokines). Immunoreactive IL-1b(ELISA) and its mRNA have been detected in rat anterior pituitary and bothare increased following LPS treatment (85, 151). IL-1b expression has alsobeen detected in a series of human pituitary adenomas in vitro (64, 136, 156).LPS treatment increases pituitary IL-1b expression while decreasing IL-1Rexpression, demonstrating that they are under reciprocal regulation (151).

TABLE 2

Summary of the Expression and Action of Cytokines in the Pituitary Gland

Cytokine

Cytokine Receptor

Regulation

Hormone secretion Cell growth

NormalCellline

Ade-noma Normal

Cellline

Ade-noma Normal

Cellline

Ade-noma Normal

Cellline

Ade-noma

IL-1/IL-1ra 1 NR 1 1 1 NR T1 T1 T1 < 2 NRIL-2 NR 1 1 1 1 1 T1 T1 NR < > ><

IL-6 1 1 1 1 NR NR T1 T1 NR < > ><

LIF 1 NR 1 1 1 1 T1 T1 NR > < NRMIF 1 NR NR NR NR NR NR NR NR NR NR NRTGF-b 1 NR 1 NR 1 NR T1 T1 NR NR NR NRTNF-a NR NR 1 NR 1 NR T1 T1 NR NR NR NRIFN-g NR NR NR NR NR NR T1 NR T1 NR NR NR

Note. Evidence about cytokine and receptor expression and action (regulation of hormonesecretion and growth), according to the literature stated in the text, is summarized in this table. (1)

80 ARZT ET AL.

Protein and/or mRNA detected; (T1) a detailed description about the actions on the differenthormones is displayed in Table 1. NR, not reported; (2) no action; (>) stimulation; (<) inhibition; (><)stimulation and inhibition.


IL-1ra, an IL-1 endogenous competitive peptide antagonist at the IL-1R, hasbeen demonstrated in the rat anterior pituitary by RT–PCR (61). IL-1ra hasalso been detected by RT–PCR and immunofluorescence in several types ofhuman pituitary adenomas (134). Both IL-1 and IL-1ra increase in the pitu-itary, as well as in other tissues, after LPS treatment of mouse (59).

IL-6 production by anterior pituitary cells has been demonstrated by severalgroups (146, 164), as has been the presence of IL-6 mRNA in these cells (145).The production of IL-6 by these cells can be increased by many compounds,including IL-1 (142, 144, 175), PMA and LPS (145, 146), VIP (141), forskolin(141), interferons (174), TNF-a (111), and PACAP (155). It is of interest to notethat activators of both the protein kinase A and C pathways appear to increasethe production of IL-6 by anterior pituitary cells. Glucocorticoids inhibit theproduction of IL-6 by anterior pituitary cell (141) and aggregate cultures (36).Levels of IL-6 mRNA are increased after adrenalectomy in the rat, suggestingthe presence of negative feedback from the HPA axis end product on IL-6production by the pituitary (137). IL-6 production has been localized to FS cellsof the pituitary (164, 165). The FS cell line obtained from a pituitary thyrotropictumor, TtT/GF, releases IL-6 in response to VIP, PACAP (102), and TNF-a (84).

IL-6 mRNA has been detected in human corticotrophic adenoma cell cultures(168) as well as in normal human pituitaries and other adenoma types (i.e.,prolactinomas, nonfunctioning adenomas, and somatotropinomas) by in situhybridization (76, 169). Tsagarakis et al. used immunocytochemistry to detectthe presence of IL-6 in 14 of 15 of pituitary adenomas of different types (159).Jones et al. have shown that immunoreactive and bioactive IL-6 are secreted byall types of pituitary tumors cultured in vitro (76, 77). By RT–PCR, IL-6 mRNAwas observed in pituitary adenomas of different types (64). Additionally, IL-1 isable to stimulate the release of IL-6 from cultures of pituitary adenomas (79). Ithas been shown that IL-6 expression may correlate with biological aggressionin pituitary adenomas (159).

In AtT-20 cells IL-2 mRNA was detected after stimulation with CRH or PMA.Similarly, IL-2 mRNA and the secretion of immunoreactive IL-2 were detectedin human corticotrophic adenoma cells; this expression and secretion could bestimulated by PMA (12). By RT–PCR IL-2 mRNA was also detected in freshadenoma tissue but not in primary culture (156).

TNF-a gene expression has been demonstrated by RT–PCR in pituitaryadenoma tissue and culture (64, 156). No evidence is available at this time toindicate that interferon-g is synthesized in the pituitary.

TGF-b was found in normal human anterior pituitary (67) and, by RT–PCR,in pituitary adenomas (64, 156). TGF-b immunoreactivity was detected inconnective tissue and in endothelial cells but not in any secretory cell (129). Itmay be possible that TGF-b produced by pituitary cells is immediately releasedto the extracellular matrix, but the demonstration of TGF-b biosynthesis byanterior pituitary cells is still lacking.


LIF has been shown to be secreted by bovine pituitary follicular cells inculture (56). LIF protein and mRNA have been demonstrated in the developinghuman fetal pituitary and in normal and adenomatous adult human tissue (4).


In pituitary explant cultures LIF mRNA was detected and increased by proteinsynthesis inhibitors (37). Mouse LIF mRNA was also induced by LPS intraperi-toneal injection, to a greater extent than LIF receptor mRNA (170).

MIF is expressed in the pituitary and this expression increases after LPStreatment (21).

CYTOKINE REGULATION OF ANTERIOR PITUITARY PROLIFERATIONAND GROWTH

Pituitary adenomas are thought to originate by somatic mutation and clonalexpansion of a single cell (5, 30). Whether a disturbed autocrine/paracrineregulation triggers the mutation is not clarified in the cascade of pathogenesis.However, the tumor cell clearly has the potential for the autocrine/paracrineregulation of proliferation and neovascularization as the most important stepsin that cascade.

In addition to the effects on the secretion of pituitary hormones describedabove, cytokines can influence the growth of pituitary cells (Table 2). Wedemonstrated that IL-2 and IL-6 can regulate pituitary cell growth (10). In theGH3 cell line both IL-2 and IL-6 significantly stimulate [3H]thymidine incorpo-ration and cell number, yet the same concentrations of IL-2 and IL-6 inhibit thegrowth of normal rat pituitary cells (10, 11). No direct correlation betweengrowth effects and hormone secretion were observed in these studies. Thestimulatory effect of IL-2 on the growth of GH3 cells is blocked by antiestro-gens, and IL-2 stimulates transfected estrogen response elements in thesecells, suggesting cross-talk between the estrogen receptor and IL-2 signaltransduction (113). IL-2 has also been reported to stimulate growth of GH-producing adenomas in vitro (90) and IL-6 has been reported to stimulategrowth of TtT/GF cells (130) as well as the proliferation of the MtT/E rat tumorpituitary cell line (135). Accordingly, the pituitary folliculostellate cell lineTtT/GF, which, as stated above, also expresses IL-6 (102), has been shown tostimulate somatotropic tumor cell (MtT/S) pituitary tumor growth in nude mice(89). IL-1a and IL-1b inhibit anterior pituitary cell growth, an effect antago-nized by IL-1ra, but do not act on GH3 cells (131). LIF released from primarybovine pituitary cultures was shown to suppress the proliferation of aorticendothelial cells and is, therefore, considered as a factor regulating pituitaryangiogenesis (56). LIF also regulates proliferation of specific hormone-producing cells; it inhibits AtT-20 cell growth, including cell number, viablemitochondria number, bromodeoxyuridine incorporation, and S phase entry(149). IL-2 increases c-myc transcription and, dose-dependently, DNA replica-tion in AtT-20 cells (124). TGF-b has been shown to inhibit GH4 cell prolifera-tion (127).

82 ARZT ET AL.

Adenoma cells in culture do not express c-fos mRNA. In adenoma explants,however, immediate early gene c-fos expression was detected and was regu-lated by IL-2 or IL-6. This might indicate that cell–cell interactions and


interleukin expression are important for the control of c-fos expression and,hence, for the control of cell proliferation in the pituitary gland. In differenttumors (ACTH-, PRL-, and GH-secreting and nonfunctioning adenomas), theseinterleukins had inhibitory or stimulatory effects but the kind of response doesnot seem to be associated to tumor type or size. Using blocking antibodies, as afunctional assay for intrapituitary action, we observed that intrinsic IL-2 andIL-6 regulate c-fos expression in the same way (118). Accordingly, IL-6 has beenalso shown to stimulate proliferation in some pituitary adenomas, while not inothers (78). The differences observed in the effects of these interleukins on c-fosgene expression among different adenomas may reflect some molecular differ-ences, such as mutations affecting second messenger pathways that may occurduring pituitary tumorigenesis. These could underlie different stages of tumordevelopment in which the autocrine/paracrine growth regulation may changefrom inhibition to stimulation. Gelatinase activity, involved in aggressivetumor invasion and metastasis, is highly regulated in pituitary tumor cells bydifferent cytokines and hypothalamic factors, while normal pituitary cells donot show such regulation (M. Paez Pereda, E. Arzt, G.K. Stalla, unpublisheddata). These changes in the gelatinase response to cytokines further supportthe hypothesis of molecular changes during adenoma transformation thataffect cytokine signal transduction.

All together, these results show that, as in other cell types, IL-1 (and IL-1ra),IL-2, IL-6, and LIF in pituitary cells may be autocrine/paracrine active growth/inhibiting factors.

GROWTH FACTORS: SUMMARY OF FUNCTION AND SOURCES OF SEVERALGROWTH FACTORS INVOLVED IN CELL TO CELL COMMUNICATION

IN THE ANTERIOR PITUITARY GLAND

The pituitary gland is not only a target but also a source of numerous otherpolypeptide growth factors that influence the function and growth of anteriorpituitary cells. The production of growth factors and the expression of theirreceptors in the same tissue would allow polypeptide growth factors, as shownin this review of cytokines, to act in an auto- or paracrine manner indepen-dently of extrapituitary, circulating growth factors. Intrinsically producedpolypeptide growth factors may directly influence hormone secretion andpituitary cell proliferation or may act indirectly by altering other intrinsicallyexpressed growth factor systems involved in pituitary function and growth. Inaddition, altered expression of intrinsic polypeptide growth factors or theirreceptors in pituitary adenomas point to a possible involvement of these growthfactors in pituitary tumorigenesis. These other growth factors, IGF-I andIGF-II, NGF, EGF, TGF-a, FGF, VEGF, and PDGF, acting in the pituitary have


been extensively reviewed elsewhere (51, 132). No studies have been performedregarding the putative interaction of these growth factors and cytokines in theregulation of pituitary pathophysiology.


THE CONCEPT OF CYTOKINE/GROWTH FACTOR AUTOCRINE/PARACRINENETWORKS IN ANTERIOR PITUITARY PHYSIOLOGY AND PATHOLOGY

The above-reviewed observations demonstrate that IL-1, IL-1R, and IL-1raare expressed in the anterior pituitary and that this expression changes inresponse to the activation of the immune system. The observations also suggestthat IL-6 is both produced in the pituitary and able to influence the secretion ofanterior pituitary hormones, consistent with a paracrine or autocrine model forIL-6 action within the pituitary. As required for an autocrine or paracrine factorIL-2 receptor, production, function, and regulation have been described in theanterior pituitary. For both IL-2 and IL-6, assays with neutralizing antibodiesdemonstrated a role for the intrinsically produced cytokines. LIF and LIFreceptor gene expression and regulation as well as LIF action on both functionand growth have been convincingly demonstrated. Thus, the data reviewedabove clearly demonstrate that IL-1 (and IL-1ra), IL-2, IL-6, LIF, and theirrespective receptors are expressed in the pituitary and are able to influence thegrowth and function of pituitary cells (Table 2). The inflammatory cytokinesIL-1 and IL-6 as well as the related cytokine LIF increase following aninflammatory stimulus, like LPS. All together, these observations fulfill ourcriteria for autocrine or paracrine regulators of pituitary growth and function.Moreover, these cytokines are also expressed in pituitary adenomas and regu-late pituitary cell proliferation both in adenomas and normal tissue. This fact,considering the small proliferation of the pituitary gland, underlies their roleas one of the factors controlling pituitary cell division.

For cytokines like TNF-a, IFN-g, and TGF-b not all the pieces of informationrequired to rule in or out autocrine or paracrine effects are in place (Table 2).Ongoing investigation will certainly provide us with additional information inthe near future. Cytokines involved in inflammatory-macrophage-derived pro-cesses (i.e., IL-1, IL-1ra, IL-6, TNF-a, TGF-b, LIF, and MIF) and on Th1processes (i.e., IL-2, interferon-g, and also LIF and TNF-a) are expressed andact on the anterior pituitary. No evidence is available at all about the involve-ment of Th2 cytokines such as IL-4, IL-5, IL-10, and IL-13. Those cytokinesinvolved in pituitary physiology are inhibited by glucocorticoids (also, in thefew studies performed with this steroid regarding cytokines in the pituitary),while the Th2 cytokines are stimulated by glucocorticoids. The feedback inhibi-tory action of glucocorticoids on the pituitary, as well as on Th1/inflammatorycytokines (also in the pituitary), and its shift toward Th2 cytokines (126) whichdo not act on the pituitary seem to be a coordinated homeostatic mechanism.

Some open questions regarding the cytokine network in the pituitary remainto be clarified in the future: (1) Putative production of IL-2 and other cytokinesby normal anterior pituitary cells has not been demonstrated and remains anopen question. (2) Few studies have focused on the interaction of cytokines inpituitary physiology. As shown in the immune system it is very likely that

84 ARZT ET AL.

cytokines interact at multiple levels in the anterior pituitary gland, a fact thatremains to be explored. Studies on the putative interaction with growth factorsshould also be performed to establish their role in pituitary adenoma pathogen-


esis. (3) Only for LIF have studies been performed on the pituitary of geneti-cally modified animals, transgenic or KO. Such studies will surely increase ourknowledge about the role of cytokines in the pituitary. (4) Further informationabout the mechanisms of action (i.e., second messengers, transcription factors)of cytokines on pituitary function and growth is needed.

Autocrine (and paracrine) secretion of growth factors is a concept providing aunifying theme in the search for the molecular and cellular basis of malignanttransformation. The cytokine network certainly provides a clue for understand-ing the growth properties of the anterior pituitary gland. A role of TGF-bproduction and receptor expression in the growth of different cell types hasbeen demonstrated, constituting one confirmation of the hypothesis that cellsmay produce their own inhibitors of growth (138). Soluble factors derived fromnormal fibroblasts have been observed to have antithetical growth effects onmetastatic versus metastatically incompetent tumors (42). Similarly, IL-6produced by fibroblasts has been proposed to play a paracrine role in theinhibition of breast cancer cell growth (1, 2). This phenomenon, in fact, occursalso in other tumor cell types, in which IL-6 can switch from behaving as aparacrine growth inhibitor to a growth stimulator during the progression fromearly stage metastatically-incompetent melanoma cells to advanced stagemetastatically-competent cells (93, 94). IL-6 production by FS cells in thepituitary (which are found surrounding adenomas) (146, 164) could play asimilar role. Considering that the uncontrolled division of cells may resulteither from excessive growth stimulation or deficient growth inhibition, theregulation of pituitary cell growth by cytokines, together with their intrinsicpituitary production, might implicate these cytokines in the process of pituitarytumor initiation or maintenance.

IL-1, IL-2, IL-6, and LIF production and the expression of their receptors onpituitary cells together with their stimulatory/inhibitory effects on pituitarycell proliferation strongly suggest that these cytokines could be involved in theprocess of tumor formation in the anterior pituitary. The particular factorsinvolved in the development of different types of pituitary tumors (micro–macroadenomas, invasive, metastatic) as well as those responsible for the highincidence of nonmalignant pituitary tumors are not clear at present. Humanpituitary adenomas have paradoxical features, such as seldom producingmetastasis and invasion, despite of their high incidence, high levels of gelatin-ase activity, and occurring in a highly vascularized organ. Cytokine expressionwithin the gland constitutes an excellent natural model for exploring theiraction and their rationale in genetic therapy and for discovering if they areinvolved in the fact that, despite the permissive factors for invasion andmetastasis, human pituitary tumors have low invasive ability and rarelymetastasize. Transfections of tumor cells with interleukin genes have beenshown to be effective in inhibiting some metastatic tumors (34, 38, 49, 97, 106).Taking into account the special characteristics of pituitary adenomas (particu-


larly the virtual absence of metastatic tumors), clarifying the role of interleu-kins in a physiological switch that may occur during pituitary cell transforma-tion and adenoma development may be important not only for understanding


anterior pituitary tumor development but also be of interest for anteriorpituitary tumor therapy.

ACKNOWLEDGMENTS

This work was supported by grants from the Volkswagen Foundation (I/74 149), the Commissionof the European Communities (93.6014.AR/CI1*-CT93-0092), the Deutsche Forschungsgemein-schaft (Sta 285/7-3), the University of Buenos Aires (UBA) and the CONICET-Agencia Nacional dePromocion Cientıfica y Tecnologica-Argentina.

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Pathophysiological Role of the Cytokine Network in the Anterior Pituitary Gland

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