Localization of Macrophage Migration Inhibitory Factor (MIF) to Secretory Granules within the Corticotrophic and Thyrotrophic Cells of the Pituitary Gland

Abstract

Background: Macrophage migration inhibitory factor (MIF) was one of the first lymphokine activities to be discovered and was described almost 30 years ago to be a soluble factor(s) produced by activated T lymphocytes. In more recent studies, MIF has been "rediscovered" to be an abundant, pre-formed constituent of the anterior pituitary gland and the macrophage, and to be a critical component in the host response to septic shock. Pituitary-derived MIF enters the circulation after infectious or stressful stimuli and appears to act to counterregulate glucocorticoid suppression of cytokine production. Materials and Methods: Immunoelectron microscopy utilizing a combination of anti-MIF and anti-pituitary hormone-specific antibodies was used to study the ultrastructural localization of MIF within the anterior pituitary gland. Pituitaries were obtained from resting, unstimulated mice and from mice 16 hr after endotoxin administration. The release of MIF also was investigated in vitro by examining the effect of corticotropin-releasing hormone (CRH) on the AtT-20, corticotrophic cell line.Results: MIF localizes to granules present exclusively in ACTH and TSH secreting cells. Within each cell type, a subset of granules was found to contain both MIF and ACTH, or MIF and TSH. The pituitary content of MIFcontaining granules decreased significantly after experimentally induced endotoxemia. In seven pituitaries examined 16 hr after LPS injection, the number of MIFpositive granules diminished by 38% in corticotrophic cells and by 48% in thyrotrophic cells when compared with controls (p < 0.05). CRH was observed to be a potent MIF secretagogue in vitro, inducing the release of MIF from corticotrophic cells at concentrations lower than that required for ACTH release. Conclusion: These data provide ultrastructural information that identify MIF to be a novel anterior pituitary hormone, support earlier studies showing a time-dependent release of pituitary MIWF during endotoxemia, and suggest an important, systemic role for MIF in the stress response to infection and other stimuli. years, however, the specific biological functions of MIF were unknown, and an appreciation of the important physiological role of this protein has emerged only recently. For instance, significant quantities of pre-formed MIF protein have been identified to be present in the anterior pituitary gland and in monocytes/macrophages and to be released into the bloodstream in response to invasive stimuli (3,4). MIF plays a pivotal role in the host response to endotoxic shock, 781 782

A functional promoter polymorphism in the macrophage migration inhibitory factor (MIF) gene associated with disease severity in rheumatoid arthritis

“…36 Of note, the anterior pituitary gland has been shown to be an important source of MIF in rodents, 3 and secretes MIF in response to physiological or infective stress. 37,38 While there is some evidence that the hypothalamic-pituitary-adrenal (HPA) axis may play a role in the pathogenesis of rheumatoid arthritis in certain patients, 39 MIF does not appear to colocalize in the pituitary gland with the known expression pattern of Pit-1. 36,38,40 Since the initiation of these studies, a −173*G/C single nucleotide polymorphism (SNP) in the Mif gene promoter has been reported by Donn et al 41 and was shown to be associated with systemic-onset juvenile idiopathic arthritis (systemic-onset JIA).…”

Insulin secretion is regulated by the glucose-dependent production of islet β cell macrophage migration inhibitory factor

“…Recent studies have identified MIF to be a new pituitary peptide that colocalizes to the ACTH and TSH secretory granules of the corticotrophic and thyrotrophic cells (3,5). MIF is released from the pituitary gland upon activation of the hypothalamic-pituitary-adrenal axis and contributes to the increase in the serum concentration of MIF during endotoxemia and stress (3,6).…”

“…A much broader role for MIF has recently emerged from studies that have identified this protein to be an abundant preformed constituent of the anterior pituitary gland and of monocytes͞macrophages (3,4). MIF is colocalized with corticotropin (ACTH) and thyroid stimulating hormone (TSH) in the secretory granules of corticotrophic and thyrotrophic cells of the pituitary gland and is released into the bloodstream in response to various proinflammatory stimuli (5). MIF plays a pivotal role in the host response to endotoxic shock, and the administration of neutralizing anti-MIF antibodies fully protects animals from lethal endotoxemia (3).…”

In Vivo Blockade of Macrophage Migration Inhibitory Factor Ameliorates Acute Experimental Autoimmune Encephalomyelitis by Impairing the Homing of Encephalitogenic T Cells to the Central Nervous System

“…Among the soluble mediators regulating the expression of these molecules is a 12.5-kDa protein known as macrophage migration inhibitory factor (MIF). MIF was one of the first cytokines described, and is secreted by activated T cells, macrophages, and a variety of nonimmune cells (7)(8)(9)(10). MIF was recently cloned and shown to have a plethora of immunologic activities, including the inhibition of migration and enhanced TNF-␣ and NO production by macrophages (11,12).…”