Role of stromal cell-derived factor 1 (SDF1/CXCL12) in regulating anterior pituitary function

Abstract

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.

Overexpression of Stromal Cell–Derived Factor 1 and Its Receptor CXCR4 Induces Autocrine/Paracrine Cell Proliferation in Human Pituitary Adenomas

“…We previously showed an autocrine/ paracrine mitogenic activity of SDF1 in cell lines and primary cultures of human glioblastoma multiforme coexpressing CXCR4 (16,18). In the present study, most of pituitary adenomas showed a similar pattern of coexpression, suggesting In addition, the high percentage of human pituitary adenomas expressing CXCR4 suggests that alterations of CXCR4 activity, possibly via a deregulated SDF1 secretion from the adenomatous cells themselves, the hypothalamus, or directly coming from the bloodstream (26), may contribute to the clonal expansion of transformed pituitary cells.…”

“…More recently, chemokines acquired a relevant role in the physiology, pathology, and tumor transformation of different cell types, although, to date, few studies addressed their role in the regulation of normal and tumor pituitary cell functions (26). For example prosecretory effects of GRO (member of the IL-8 family) in rat anterior pituitary cells were reported (39).…”

“…In rat anterior pituitary, the expression of CXCR4 mRNA, as well as SDF1-binding sites, were reported (24,25). Still, the cellular distribution of SDF1-and CXCR4-expressing cells in rodent pituitary is unclear and no data are presently available about their expression and physiologic role in human normal pituitary or their role in pituitary adenoma pathogenesis (26).…”

CXCR7 is an active component of SDF-1 signalling in astrocytes and Schwann cells

“…Outside the hematopoietic system, SDF-1 is essential for cardiogenesis, vascularization of the gastrointestinal tract, limb myogenesis, and morphogenesis of the central and peripheral nervous systems (CNS and PNS) (Ma et al, 1998;Zou et al, 1998;Tachibana et al, 1998;Li and Ransohoff, 2008;Ödemis et al, 2005). In the adult nervous system, expression of SDF-1 and its receptor, CXCR4, persists in astrocytes, microglial cells, Schwann cells, distinct neuronal populations and endothelial cells (Li and Ransohoff, 2008), modulating neurotransmitter release from neurons and glia as well as hormone secretion from neuroendocrine cells (Bezzi et al, 2001;Barbieri et al, 2007;Lazarini et al, 2003;Rostène et al, 2007). SDF-1 and CXCR4 are additionally involved in several brain pathologies, such as acute ischemic and traumatic brain injuries, chronic brain infections and autoimmune diseases (Cartier et al, 2005;Li and Ransohoff, 2008).…”

Neutrophil Elastase, Proteinase 3, and Cathepsin G as Therapeutic Targets in Human Diseases

“…SDF-1␣ plays a critical role in cell migration because it is a chemotactic factor for T cells, monocytes, pre-B cells, dendritic cells, and hematopoietic progenitor cells (Barbieri et al, 2007). Gene inactivation of SDF-1␣ or of its receptor CXCR4 in mice impairs myelo-and lymphopoiesis Odemis et al, 2005).…”