Macrophage Migration Inhibitory Factor (MIF): A Glucocorticoid Counter-Regulator within the Immune System

Abstract

Originally described as a T lymphocyte-derived factor that inhibited the random migration of macrophages, the protein known as macrophage migration inhibitory factor (MIF) was an enigmatic cytokine for almost 3 decades. In recent years, the discovery of MIF as a product of the anterior pituitary gland and the cloning and expression of bioactive, recombinant MIF protein have led to the definition of its critical biological role in vivo. MIF has the unique property of being released from macrophages and T lymphocytes that have been stimulated by glucocorticoids. Once released, MIF overcomes the inhibitory effects of glucocorticoids on TNFα, IL-1β, IL-6, and IL-8 production by LPS-stimulated monocytes in vitro and suppresses the protective effects of steroids against lethal endotoxemia in vivo. MIF also antagonizes glucocorticoid inhibition of T-cell proliferation in vitro by restoring IL-2 and IFN-γ production. This observation has identified a pivotal role for MIF within the immune system and fills an important gap in our understanding of the control of inflammatory and immune responses. Glucocorticoids have long been considered to be an integral component of the stress response to infection or tissue invasion and serve to modulate inflammatory and immune responses. MIF is the first mediator to be identified that can counter-regulate the inhibitory effects of glucocorticoids and thus plays a critical role in the host control of inflammation and immunity.

Relative Adrenal Insufficiency in Pediatric Septic Shock

“…50 All these effects, considered stimulatory corticosteroids effects, have been observed at lower steroid concentrations, whereas higher steroid concentrations produced no effect or suppressive effects. [51][52][53][54][55][56][57] In addition, the concentration of cortisol that is needed to effectively suppress ongoing systemic inflammation in vivo remains a matter of controversy. 58…”

Hepatocyte-derived IL-10 plays a crucial role in attenuating pathogenicity during the chronic phase of T. congolense infection

“…Hence, therapeutic approaches that tilt the balance of "hepatocyte" cytokine production in favour of IL-10 are likely to majorly impact the wellbeing and survival of T. congolense-infected animals. Given that, in contrast to IL-6, MIF is an upstream regulator of the inflammatory cascade whose blockade may be more efficient at attenuating the inflammatory immune response [40]. This notion was strengthened by the fact that interfering with MIF signaling using a Nb-based approach indeed attenuates the excessive inflammatory immune response as well as the most prominent pathological feature associated with T. congolense infections, i.e.…”

“…In this respect, we have reported before that MIF plays a key role in T. congolense infection associated pathogenicity [39] and we demonstrated here that MIF levels were significantly upregulated in TgAlbCre-IL10 -/mice during later stages of infection both systemically and in the liver (Figs 3 and 10A). Moreover, in contrast to IL-6, MIF is an upstream regulator of the inflammatory cascade whose blockade may be more efficient at attenuating the inflammatory immune response [40]. Hence, we evaluated whether neutralization of MIF, using a half-life extended anti-MIF Nb [39], could attenuate the pathology observed in TgAlbCre-IL10 -/mice.…”

Pituitary Hyperplasia, Hormonal Changes and Prolactinoma Development in Males Exposed to Estrogens—An Insight From Translational Studies

“…On the other hand, glucocorticoids stimulate secretion of macrophage migration inhibitory factor (MIF) by folliculo-stellate cells, macrophages and T lymphocytes. MIF has been identified in the pituitary gland, and this counter-regulates the inhibitory effects of glucocorticoids on TNFα, IL-1β, IL-6 and IL-8 production [120]. Therefore, attenuated glucocorticoid signaling may actually promote prolactinoma development and/or progression by affecting its cellular microenvironment.…”