Macrophage Migration Inhibitory Factor Is Released from Pituitary Folliculo-Stellate-Like Cells by Endotoxin and Dexamethasone and Attenuates the Steroid-Induced Inhibition of Interleukin 6 Release

Abstract

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine produced by peripheral immune cells and also by endocrine cells in the anterior pituitary gland. MIF exerts its proinflammatory actions in the host-defense system by blocking the inhibitory effects of glucocorticoids on the release of other proinflammatory cytokines (e.g. IL-1, IL-6, TNFalpha). Reports that pituitary folliculo-stellate (FS) cells share many characteristics with immune cells led us to propose that these cells may serve as an additional source of MIF in the pituitary and that pituitary-derived MIF may act in an autocrine or paracrine manner to modulate endotoxin-induced cytokine release from FS cells. In the present study we addressed this hypothesis by using 1) immunohistochemistry to localize MIF in primary pituitary tissue and 2) well-characterized FS (TtT/GF), corticotroph (AtT20), and macrophage/monocyte (RAW 264.7) cell lines to explore the effects of CRH, endotoxin, and dexamethasone on MIF release and to examine the effects of MIF on IL-6 release. Our immunohistochemical study showed that MIF is expressed in abundance in S100-positive FS cells and also in other pituitary cell types. All three cell lines expressed MIF protein and responded to endotoxin (10-1000 ng/ml, 24 h) and dexamethasone (100 pM to 10 nM, 24 h) with concentration-dependent increases in MIF release. CRH (10-100 nM) also stimulated MIF release from AtT20 cells but, unlike endotoxin and dexamethasone, it had no effect on MIF release from TtT/GF or RAW cells. Recombinant MIF did not affect the basal release of IL-6 from TtT/GF cells; however, it effectively reversed the inhibitory effects of dexamethasone (1 nM) on the endotoxin-induced release of IL-6 from these cells. The results suggest that the FS cells are both a source of and a target for MIF and raise the possibility that MIF serves as a paracrine/autocrine factor in the pituitary gland that contributes to the protective neuroendocrine response to endotoxin.

History and perspectives of pituitary folliculo-stellate cell research

“…Very recently, Tierney et al (14) found immunoreactivity to the proinflammatory cytokine MIF in part of the S-100…”

“…A still growing list includes S-100 (54), bFGF (9), VEGF and follistatin (10, 11), IL-6 (13, 53, 81), LIF (12), MIF (14) and IL-10 (86). FS cells were indicated as the most plausible source of (most of) the latter growth factors and cytokines, although, for instance in human pituitary adenomas, evidence was provided that S-100 þ FS cells were not the major source of Il-6 (87).…”

“…FS cells were found to be a source of newly discovered growth factors and peptides such as basic fibroblast growth factor (bFGF) (9), vascular endothelial growth factor (VEGF) (10,11) and follistatin (11), as well as of cytokines such as leukemia inhibitory factor (LIF) (12), interleukin (IL)-6 (13) and macrophage migration inhibitory factor (MIF) (14). FS cells were also shown to respond to b-adrenergic stimuli and displayed enhanced cAMP-accumulation upon b-adrenergic stimulation (15).…”

“…FS cells were also shown to respond to b-adrenergic stimuli and displayed enhanced cAMP-accumulation upon b-adrenergic stimulation (15). Some groups have studied in more detail the involvement of FS cells in dipeptide uptake mechanisms (16), or their role in a local pituitary cytokine network (13,14,17). Finally, their role in the production of the radical nitric oxide (NO) and in NO signaling (18 -20) brought them into the limelight again when the role of NO in the regulation of pituitary hormone secretion was discovered (18,21).…”

Adenosine regulates thrombomodulin and endothelial protein C receptor expression in folliculostellate cells of the pituitary gland

“…In addition to modulating hormone secretion in the anterior lobe [11,12], these cells seem to play a central role in co-ordinating the interplay between the immune and endocrine systems [13]. The recent demonstration of macrophage migration inhibitory factor expression and secretion in cultured FS cells [14], and its modification by glucocorticoids, supports this contention. We have previously shown that adenosine can stimulate IL-6 production in cultured FS cells, an effect mediated via the A2b adenosine receptor subclass and involving activation of p38 MAP kinase [15,16].…”