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Section of Pharmacology, Department of Oncology Biology and Genetics, University of Genova, Viale Benedetto XV, 2, 16132 Genova, Italy

(Requests for offprints should be addressed to T Florio; Email: tullio.florio{at}unige.it)

	Abstract

Top Abstract Role of chemokines in... Chemokine modulation of normal... Pituitary and hypothalamic... Biological effects of SDF1... Intracellular mechanisms... Conclusions References

 
Chemokines are key factors involved in the regulation of immune response, through the activation and control of leukocyte traffic, lymphopoiesis and immune surveillance. However, a large number of chemokines and their receptors are expressed in central nervous system (CNS) cells, either constitutively or induced by inflammatory stimuli, playing a role in many neuropathological processes. Stromal cell-derived factor 1 (SDF1) is a chemokine whose extra-immunological localization and functions have been extensively studied. SDF1 and its receptor CXCR4 were identified in both neurons and glia of many brain areas, including the hypothalamus, as well as at the pituitary level. Importantly, SDF1 and CXCR4 expression is increased in brain tumors in which their activity induced tumor cell proliferation and brain parenchyma invasion. Despite their localization, to date very few reports addressed the role of CXCR4 and SDF1 in the modulation of the hypothalamus/pituitary axis and their possible involvement in the development of pituitary adenomas. In this review, we discuss previous literature data on the role of chemokines in normal and adenomatous pituitary cells, focusing on recent data from our group showing that CXCR4 activation controls proliferation and both prolactin and GH release in the pituitary adenoma cell line GH4C1 through a complex network of intracellular signals. Thus, the SDF1/CXCR4 system together with other chemokinergic ligand–receptor pairs, may represent a novel regulatory pathway for pituitary function and, possibly, be involved in pituitary adenoma development. These lines of evidence suggest that the inhibition of chemokine receptors may represent a novel pharmacological target for the treatment of pituitary adenomas.

	Role of chemokines in neuroendocrine regulation

Top Abstract Role of chemokines in... Chemokine modulation of normal... Pituitary and hypothalamic... Biological effects of SDF1... Intracellular mechanisms... Conclusions References

 
Stromal cell-derived factor 1 (SDF1), also called CXCL12, is a chemokine of the CXC subfamily originally characterized as a pre-B-cell stimulatory factor and cloned from bone marrow cell supernatants. SDF1 exists in three alternative splicing variants (, ß and ), of which SDF1 is the most abundant in the brain (Nagasawa et al. 1994). The sequence of this chemokine is highly conserved among the species, with only one amino acid difference between murine and human SDF1, suggesting that this molecule may play a significant biological role. SDF1 is a chemotactic factor for T cell, monocytes, pre-B-cells, dendritic cells, and hematopoietic progenitor cells and supports B-cell progenitor and CD34⁺ cell proliferation (Luster 1998, Christopherson & Hromas 2001). However, its expression is not restricted to immune and hematic cells, but SDF1 mRNA and protein were also identified in the central nervous system (CNS) in neuronal, astroglial, microglial, and endothelial cells (Bajetto et al. 2001a). SDF1 exerts its effects via the binding to CXCR4, a receptor member of the G-protein-coupled receptor superfamily. Their interaction is reported to be unique, different from other chemokines that recognize multiple receptors. The disruption of CXCR4 or SDF1 genes in mice, causes a similar embryological lethal phenotype, characterized by deficient B-lympho- and myelopoiesis, defects in vasculogenesis and abnormal development of the heart and of different areas of the CNS (Nagasawa et al. 1996, Zou et al. 1998). Similarly to SDF1, CXCR4 is expressed outside the immune system, including endothelial cells, embryonic germinal neuroepithelium and mature neurons, astrocytes and microglia (Oh et al. 2001). Furthermore, CXCR4 was reported to represent a co-receptor of CD4 for the entry of T-lymphotropic strains of the immunodeficiency virus (HIV-1); SDF1, competing for CXCR4, can inhibit the fusion and replication of HIV-1 in CD4⁺/CXCR4⁺cells (Feng et al. 1996).

Interestingly, besides a specific distribution of both SDF1 and CXCR4 in different brain areas and neuronal subpopulations, a selective localization of SDF1 expressing neurons was detected in many hypothalamic nuclei, including the paraventricular nucleus (PVN), the lateral hypothalamus, the lateral pre-optic area and the median eminence (Banisadr et al. 2003, Guyon et al. 2005). Furthermore SDF1 was reported to inhibit arginine vasopressin (AVP) release from the magnocellular neurons of the supraoptic and the paraventricular hypothalamic nuclei in normal rat. In addition, AVP projections to the anterior pituitary co-express SDF1 and CXCR4 thus demonstrating that the SDF1/CXCR4 axis represents an autocrine system that modulates brain and neuroendocrine activity (Callewaere et al. 2006). Importantly, although the majority of the SDF1-labeled neurons belonged to the magnocellular sub-population projecting to the neurohypophysis, SDF1 expressing neurons, even though less numerous (20% of the neurons when compared with 60% in the vasopressinergic neurons), were also observed in the parvocellular part of the PVN (Banisadr et al. 2003).

	Chemokine modulation of normal pituitary function

Top Abstract Role of chemokines in... Chemokine modulation of normal... Pituitary and hypothalamic... Biological effects of SDF1... Intracellular mechanisms... Conclusions References

 
It has been known for many years that different immune-derived molecules can control pituitary hormone release. In particular, it was reported that interleukin 1 ß (IL-1ß), that is produced by hypothalamic neurons (Johnson et al. 2004) inhibit prolactin secretion from dispersed rat pituitary cells through the regulation of both cAMP production and agonist-induced Ca⁺⁺ fluxes (Schettini et al. 1990). Indeed, the expression of its receptors was detected within the mouse adenohypophysis (Cunningham et al. 1992). Moreover, IL-1ß mRNA was identified in rat pituicytes after a lipopolysaccharide (LPS) challenge, supporting the hypothesis that IL-1 ß may be involved in paracrine or autocrine regulation of pituitary function during infectious challenge (Koenig et al. 1990). However, the role of IL-1ß in the brain–endocrine–immune axis is not yet completely defined. Similarly also interleukin 6 (IL-6) is released by normal rat pituitary cells (Spangelo et al. 1990a) and its receptor was also identified in normal pituicytes in humans (Hanisch et al. 2000). The pituitary source of IL-6 was identified in the folliculostellate (FS) cells in normal tissue and a paracrine mechanism was proposed for the cytokine regulation of different pituitary hormones release, including adrenocorticotropic hormone (ACTH) and prolactin (Woloski et al. 1985, Spangelo et al. 1989).

However, to date none of these studies supported a physiological role for these cytokines in pituitary function. Indeed, it was proposed that their functional effects are mainly dependenton endotoxin challenge and thus a response to infections (Spangelo et al. 1990b).

In the past years, a better defined regulation of the hypothalamic–hypophyseal axis by some pleiotropic chemokines was identified in rat. In fact, the cytokine-induced neutrophil chemoattractant (CINC, the rat counterpart of the human growth-related oncogene, GRO) was reported to be expressed in the PVN, the posterior pituitary and the median eminence. In response to stressful stimuli (i.e. immobilization stress) CINC synthesis is highly induced in the PVN and the chemokine is released in the median eminence (Sakamoto et al. 1996) to reach CXCR2 (the GRO receptor)-expressing pituitary cells. The biological effects of CINC on pituitary cells were the stimulation of prolactin release (and slight stimulation of GH secretion) and the inhibition of luteinizing hormone (LH) and follicle stimulating hormone (FSH) secretion (Sawada et al. 1994). Importantly, CXCR2 expression was identified also in normal human pituitary cells, thus supporting the relevance of this regulatory mechanism (Tecimer et al. 2000). Furthermore, a sustained CINC secretion was also observed in a subpopulation of cultured pituitary cells (Koike et al. 1994) and by FS cells (Zhang et al. 1997). Thus, again an autocrine/paracrine intrapituitary regulation may occur via the CINC/GRO stimulation of pituitary cells expressing CXCR2. However, GRO is not the only chemokine that may be involved in the regulation of pituitary function. For example, another CXCR2 ligand, interleukin 8 (IL-8), was also identified in brain areas (PVN of the hypothalamus and hippocampus) involved in the hypothalamus–pituitary–adrenal axis. Importantly, its secretion is under the control of steroids through a feedback mechanism, thus supporting a physiological role for this chemokine in the pituitary regulation of ACTH secretion (Licinio et al. 1992).

However, the chemokinergic regulation of the hypothalamus–pituitary system is still poorly studied, and we can hypothesize that more chemokine/receptor pairs are effectively involved in its regulation both in physiology and in pathology. For example, SDF1 is emerging as a major point of convergence between immune and nervous systems. In particular, binding studies showed that at the pituitary level, high affinity SDF1-binding sites were present (Banisadr et al. 2000), and CXCR4 mRNA was identified in rat anterior pituitary explants (Bajetto et al. 1999). Thus, the concomitant expression of SDF1 in hypothalamic neurons and CXCR4 at the pituitary level, may suggest that this chemokine could represent a novel hypothalamic factor possibly contributing to the regulation of anterior pituitary function.

	Pituitary and hypothalamic chemokines in the development of pituitary adenomas

Top Abstract Role of chemokines in... Chemokine modulation of normal... Pituitary and hypothalamic... Biological effects of SDF1... Intracellular mechanisms... Conclusions References

 
Pituitary adenomas constitute up to 15% of primary intracranial tumors and are associated with significant morbidity due to local mass-related effects and/or hormone hypersecretion. Pituitary adenomas are classified according to their secretory pattern: prolactinomas represent about 30% of pituitary tumors, GH hypersecretive adenomas (GHoma) account for approximately 15%, and ACTH-secreting tumors <0%. Pituitary adenomas secreting biologically inactive hormones ( subunit of glycoproteic hormones, such as thyroid stimulating hormone (TSH), LH and FSH, or the entire gonadotropins) or derived from ‘null cells’ are defined as clinically ‘non-functioning pituitary adenomas’ (NFPAs) and represent about 30% of the total pituitary tumors. To date, most aspects of molecular pathogenesis of pituitary adenomas remain unclear since few alterations have been definitively demonstrated to be involved in their tumorigenesis (Asa & Ezzat 2002).

Genetic studies reported that pituitary adenomas have a monoclonal origin with the neoplastic initiation often related to oncogenic mutations in proteins involved in cell proliferation control. Among others, mutations were identified in the genes encoding ras, PKC, the subunit of the GTP-binding proteins Gs, (gsp) or Gi (gip). Furthermore, in some cases the over-expression of activating genes (i.e. pituitary tumor transforming gene, hpttg) or loss of tumor suppressor genes (Rb, menin, p53, p27 and p16) was identified (Spada & Lania 2002).

Nevertheless, the pathogenesis of these tumors is heterogeneous with these genetic alterations identified only in subsets of adenomas. The current hypothesis proposes that these initiating events may cause a ‘gain of function’ in the proliferative activity of single pituitary cells on which promoting factors cooperate to induce the clonal expansion (Asa & Ezzat 2002).

A multiplicity of promoting factors, such as hypothalamic hormones, locally produced growth factors (EGF, bFGF, FGF-4, NGF, TGF) and cytokines (IL-1, IL-2, IL-6), have been reported to determine pituitary tumor progression (Ray & Melmed 1997, Renner et al. 2004).

Chemokines are now recognized as mediators in several physiologic and pathologic processes, including the proliferation and invasiveness of cancer cells. However, very few studies addressed the potential role of any component of the chemokine family in regulating pituitary functions. In particular, the receptor for IL-8, CXCR2, was detected in high concentration in human pituitary adenomas (Tecimer et al. 2000), suggesting a possible participation of this chemokine in the expansion of some pituitary adenomas. Interestingly, although there is an extremely variable incidence rate among different studies, that is, 3 out of 25 according to Suliman et al.(1999) or 17 out of 17 according to Green et al.(1996), the expression of IL-8 was also identified in adenoma pituitary cells altogether with its receptor; it is thus possible to hypothesize an autocrine/paracrine pathway of activation of the tumor cells.

On the other hand, SDF1 receptor CXCR4 is the most widely expressed chemokine receptor in human malignancies and its activation by SDF1 causes proliferation, migration, invasion, and metastatization of cancer cells and promotes tumoral neo-angiogenesis (Burger & Kipps 2006). In particular, the SDF1/CXCR4 system was reported to support the survival and growth of leukemia, breast carcinoma (Balkwill 2004), and glioblastoma multiforme (GBM) cells (Rempel et al. 2000, Bajetto et al. 2006a). In vitro studies showed that SDF1 is a growth factor for GBM cells increasing their proliferation and migration (Barbero et al. 2003). In addition, it has been reported that SDF1 stimulates chemotaxis, survival and proliferation in GBM and medulloblastoma primary cell cultures and xenografted tumors (Rubin et al. 2003).

To date, the role of SDF1/CXCR4 in the pituitary function and in the genesis of pituitary adenomas has scarcely been investigated. However, the constitutive expression of the ligand and its cognate receptor in hypothalamic neurons and pituitary cells respectively, together with the powerful role demonstrated for SDF1 as tumor proliferation factor, suggest the possibility that this chemokine, via the activation of pituitary CXCR4, may act as a promoting factor for pituitary adenoma development.

	Biological effects of SDF1 in pituitary adenoma cells: the GH4C1 cell model

Top Abstract Role of chemokines in... Chemokine modulation of normal... Pituitary and hypothalamic... Biological effects of SDF1... Intracellular mechanisms... Conclusions References

 
We used the rat pituitary adenoma cell line GH4C1 to analyze the potential role of the SDF1/CXCR4 network in the regulation of pituitary function and, possibly, pituitary tumorigenensis (Florio et al. 2006). These cells represent one of the most studied model to evaluate pituitary regulation in vitro (Westendorf & Schonbrunn 1982). GH4C1 cells display a regulated release of both GH and prolactin, and a proliferative response reproducing at best in vitro that observed in pituitary adenoma cells.

Importantly, we showed that, different from most of the tumor cell lines analyzed, these cells express CXCR4 but not SDF1. This feature is particularly important, since CXCR4 is known to go through a very rapid desensitization and thus, in the presence of an endogenous release of the chemokine in a closed system (as occurs in most in vitro studies), it could be very difficult to identify the effects of the exogenous peptide.

To assess a role for SDF1 in pituitary adenoma development, we tested, in this cell model, the effects of the chemokine in the regulation of the two key features of pituitary adenoma cells, hormone release, and proliferation.

We found that low nanomolar concentrations of SDF1 caused a significant increase in both prolactin and GH secretion, although the latter was much more pronounced (+35 and +110% respectively when compared with the basal secretion of the two hormones; Table 1). This secretagogue activity was completely abolished by pretreatment with pertussis toxin or somatostatin (100 nM; Table 1). These data indicate that SDF1 activity requires the activation of a G-protein of the Gi/Go subfamily, and that its effects are responsive to inhibitory stimuli as observed in both normal pituitary and secreting adenomas. Interestingly, pertussis toxin was able to abolish both the stimulatory effects of SDF1 (Florio et al. 2006) and the inhibitory effects of somatostatin (Florio & Schettini 1996).

To evaluate the relevance of these effects for pituitary functioning, we compared them with those induced by the known physiological pituitary regulator GHRH. Interestingly, we observed that the maximal proliferation induced by GHRH, was of the same magnitude as that obtained by SDF1 (Table 1).

Very recently, we reported some preliminary results showing the expression of SDF1 and CXCR4 in human pituitary adenoma postsurgical specimens (Bajetto et al. 2006b). When confirmed these data will surely contribute to the establishment of a role for this chemokine in pituitary tumor functioning.

	Intracellular mechanisms involved in SDF1 regulation of GH4C1 pituitary adenoma cell proliferation and GH release

Top Abstract Role of chemokines in... Chemokine modulation of normal... Pituitary and hypothalamic... Biological effects of SDF1... Intracellular mechanisms... Conclusions References

 
We used GH4C1 cells to evaluate the intracellular mechanisms activated by SDF1 to induce hormone release and cell proliferation (Florio et al. 2006). We analyzed a set of intracellular mediators that were previously involved in CXCR4 effects, namely the regulation of the intracellular Ca⁺⁺ concentration, the activation of ERK1/2 and of the cytosolic Ca⁺⁺-dependent tyrosine kinase, Pyk2, and the stimulation of the large conductance, Ca⁺⁺-activated K⁺ channels BK_Ca. Interestingly, all these systems were activated following SDF1 treatment of GH4C1 cells.

Thus, using selective inhibitors on these intracellular pathways, we tried to establish a molecular ordering between the SDF1-activated second messengers. We used the cell permeable Ca⁺⁺ chelator BAPTA-AM to abolish the intracellular Ca⁺⁺ rise induced by the chemokine, the MEK inhibitor PD98059 to revert the activation of ERK1/2, salicylate to counteract Pyk2 activation, and TEA to prevent BK_Ca channel activation. We found that the SDF1-dependent regulation of intracellular Ca⁺⁺ was independent of the activation of ERK1/2, Pyk2 or BK_Ca (i.e. it was not inhibited by PD98059, salicylate or TEA) and that ERK1/2 activation lay on an independent pathway (it was not affected by BAPTA-AM, salicylate or TEA). Conversely, Pyk2 activation was Ca⁺⁺ dependent (it was blocked by BAPTA-AM, but not by PD98059 or TEA) and BK_Ca channel activity was dependent on both the SDF1-induced intracellular Ca⁺⁺ rise (it was inhibited by BAPTA-AM) and Pyk2 activation (inhibition by salicylate).

Thus, in GH4C1 cells two independent pathways activated by SDF1 were identified: the first one is Ca⁺⁺-independent and causes the activation of ERK1/2, likely through the ß subunit of Gi, as reported for many G-protein-coupled receptors, and the second one is Ca⁺⁺-dependent involving the sequential activation of Pyk2 and BK_Ca.

Using the same pharmacological approach, we tried to establish which of these pathways was involved in the control of GH release and which controls the cell proliferation induced by SDF1.

Interestingly, we found that the SDF1-induced GH release was a solely Ca⁺⁺-dependent process, since it was not abolished by the inhibitors of ERK1/2, Pyk2 or BK_Ca, but only by the Ca⁺⁺ chelator BAPTA-AM.

On the other hand, the regulation of GH4C1 cells proliferation induced by this chemokine was dependent on both the Ca⁺⁺-independent stimulation of ERK1/2 activity and the Ca⁺⁺-dependent activation of Pyk2 and BK_Ca. Importantly, each of the inhibitory compounds tested completely reverted the proliferative stimuli of SDF1, indicating that all these intracellular second messengers (Ca⁺⁺, Pyk2, BK_Ca and ERK1/2) are necessary for such an effect. The schematic representation of intracellular pathways activated by SDF1 in GH4C1 cells is depicted in Fig. 1.

	Conclusions

Top Abstract Role of chemokines in... Chemokine modulation of normal... Pituitary and hypothalamic... Biological effects of SDF1... Intracellular mechanisms... Conclusions References

	Acknowledgements

 
This work was supported by an Italian Association for Cancer Research grant to T F. The authors declare that there is no conflict of interest that would prejudice the impartiality of this scientific work.

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Top Abstract Role of chemokines in... Chemokine modulation of normal... Pituitary and hypothalamic... Biological effects of SDF1... Intracellular mechanisms... Conclusions References

 
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Received in final form 8 November 2006
Accepted 4 December 2006
Made available online as an Accepted Preprint 28 December 2006

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