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Section on Functional Neuroanatomy, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-3724
Address all correspondence and requests for reprints to: Miles Herkenham, National Institute of Mental Health, Building 35, Room 1C913, Bethesda, Maryland 20892-3724. E-mail: herkenh{at}mail.nih.gov.
An agranular cell type in the anterior pituitary first described by Rinehart and Farquhar in 1953 (1) was named the folliculo-stellate (FS) cell on the basis of appearance (agranular and stellate), location (surrounding follicles), and positive immunostaining for the S-100 protein (2). The S-100 staining feature suggests that the FS cell is neuroectodermal. However, S-100 staining has been found in tissues of lymphoid origin as well.
Early work indicated that FS cells might serve to modulate hormone production and secretion in the anterior lobe via local paracrine actions (3, 4). The interdigitation of FS cells and hormone-producing cells supported a dynamic role for intercellular communication between the two cell types (5). Gap junctions between FS cells allow synchronized excitability (6) so that long-distance communication throughout the pituitary occurs via propagated Ca2+ currents within and between FS cells (7), suggesting a mechanism by which pulsatile hormone release can occur even in denervated pituitaries.
More recent work supports a role for FS cells in the context of reciprocal communication between the immune and endocrine systems and, more specifically, local production of cytokines that influence hormonal output from the anterior lobe. The anterior lobe of the pituitary contains mostly separate, i.e. nonoverlapping, populations of dendritic cells, macrophages, and FS cells (8), all of which appear to be capable of performing immune-related functions. However, FS cells have received particular attention. Generation of a FS cell line called TtT/GF (9) has greatly facilitated work on the properties of these cells. TtT/GF cells stimulated in vitro by the endotoxin lipopolysaccharide (LPS) secrete the cytokine IL-6 via a nuclear factor 
B (NF-B)-dependent pathway (10).
Whereas most studies support the role of the hypothalamus in completing the endocrine-immune loop, early work showed that the deafferented pituitary could produce hormones in response to endotoxin challenge (11) and, more specifically, that local actions of cytokines in the pituitary can directly affect hormone release (12). Thus, LPS can stimulate ACTH release from isolated pituitary, and the action appears to require IL-6 and a mixture of pituitary cell types (13). The study published in this issue(14) offers some additional novel data along these lines.
Macrophage inhibitory factor (MIF), a proinflammatory cytokine, is classically found in lymphoid tissues but is also produced by specific pituitary cell types (15, 16). Early studies showed its striking counterregulatory properties in endocrine and immune systems: it is induced in macrophages by glucocorticoids but then acts to override glucocorticoid-mediated inhibition of LPS-induced cytokine secretion (17). These paradoxical effects identify a counterregulatory system that functions to control inflammatory responses.
In the study by Tierney et al. (14), MIF is shown by immunohistochemistry to be present in S-100-positive FS cells. In the FS (TtT/GF) cell line, LPS stimulated MIF production at 100-pM and 10-nM concentrations but not at lower or higher concentrations. The glucocorticoid dexamethasone also stimulated MIF release, a seeming paradox as proinflammatory cytokines are typically inhibited by glucocorticoids. The study goes on to show that FS cells are not just the source of MIF, but also the target of MIF. Preincubation of cells with MIF reversed the inhibitory actions of dexamethasone on LPS-stimulated IL-6 release.
The in vitro data support the hypothesis that direct actions of endotoxin on the pituitary can affect the HPA axis response to endotoxemia. In this inflammatory condition, both LPS and glucocorticoids are elevated, and, within the anterior lobe, MIF may be produced by FS cells (and corticotrophs) and act locally in a paracrine fashion to sustain ACTH release by opposing the suppressive actions of the glucocorticoids on cytokine (IL-6) release.
The study also finds that LPS elevates MIF production from two other cell lines, AtT20 cells and RAW 264.7 cells, representing corticotroph and macrophage lineages, respectively (14). Perhaps FS cells are not the only players in the local neuroimmune-endocrine interaction game. In vivo studies show that peripherally administered LPS rapidly and massively activates NF-B transcriptional activity in cells throughout the anterior and posterior lobes pituitary (Fig. 1A
). In addition, mRNAs for cytokines such as IL-1ß and TNF
are more discretely induced in both lobes, with separate induction time courses for each lobe and cytokine (18). The cellular phenotypes of the expressing cells are not known, but, on the basis of their widespread and scattered locations (Fig. 1B), it appears that only a portion of them could be FS cells, with the remainder (or majority) being macrophage-like. LPS-induced local cytokine production by FS cells and microglia/macrophages could powerfully affect corticotroph responses to inflammatory challenges as suggested in several in vivo studies focusing on the important role of local IL-6 production (19, 20). Studies using combined in vitro and in vivo approaches are needed to further clarify the role of local cytokine actions in the pituitary during endotoxemia.
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Footnotes |
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B, nuclear factor B. Received September 24, 2004.
Accepted for publication October 4, 2004.
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mitogen-activated protein kinase/nuclear factor-B pathway. Endocrinology 141:4457–4465This article has been cited by other articles:
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  W. Allaerts and H. Vankelecom History and perspectives of pituitary folliculo-stellate cell research Eur. J. Endocrinol., July 1, 2005; 153(1): 1 - 12. [Abstract] [Full Text] [PDF]
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