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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

Department of Cellular and Molecular Neuroscience (T.T., R.P., C.A.S.S., J.C.B.), Division of Neuroscience and Psychological Medicine, Faculty of Medicine, Imperial College London, London W12 0NN, United Kingdom; and Department of Internal Medicine and Pathology (L.L., R.B.), Yale University School of Medicine, New Haven, Connecticut 06520

Address all correspondence and requests for reprints to: Prof. Julia Buckingham, Department of Cellular and Molecular Neuroscience, Division of Neuroscience and Psychological Medicine, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, United Kingdom. E-mail: j.buckingham{at}imperial.ac.uk.

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, TNF). 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.

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