LOCALIZATION OF MACROPHAGE-MIGRATION INHIBITORY FACTOR (MIF) TO SECRETORY GRANULES WITHIN THE CORTICOTROPIC AND THYROTROPIC CELLS OF THE PITUITARY-GLAND

Background: Macrophage migration inhibitory factor (MIF) was one of th e first lymphokine activities to be discovered and was described almos t 30 years ago to be a soluble factor(s) produced by activated T lymph ocytes. 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 infe ctious or stressful stimuli and appears to act to counterregulate gluc ocorticoid 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 ultrastru ctural localization of MIF within the anterior pituitary gland. Pituit aries were obtained from resting, un stimulated mice and from mice 16 hr after endotoxin administration. The release of MIF also was investi gated in vitro by examining the effect of corticotropin-releasing horm one (CRH) on the AtT-20, corticotrophic cell line. Results: MIF locali zes to granules present exclusively in ACTH and TSH secreting cells. W ithin each cell type, a subset of granules was found to contain both M IF and ACTH, or MIF and TSH. The pituitary content of MIF-containing g ranules decreased significantly after experimentally induced endotoxem ia. Ln seven pituitaries examined 16 hr after LPS injection, the numbe r of MIF-positive granules diminished by 38% in corticotrophic cells a nd by 48% in thyrotrophic cells when compared with controls (p < 0.05) . CRH was observed to be a potent MTF secretagogue in vitro, inducing the release of MIF from corticotrophic cells at concentrations lower t han that required for ACTH release. Conclusion: These data provide ult rastructural information that identify MIF to be a novel anterior pitu itary hormone, support earlier studies showing a time-dependent releas e of pituitary MIF during endotoxemia, and suggest an important, syste mic role for MIF in the stress response to infection and other stimuli .