Macrophage Migration Inhibitory Factor: A Therapeutic Target Across Inflammatory Diseases

Alberta   Y.   Hoi; Magdy   N.   Iskander; Eric   F.   Morand

doi:10.2174/187152807781696455

Abstract

Macrophage migration inhibitory factor (MIF), a cytokine originally reported in the 1960s as the prototypic T lymphokine, has emerged in recent years as a key factor regulating inflammatory responses. Both by directly activating immune cells, and by participating in activation entrained by other stimuli, MIF is important in innate and adaptive immune responses as well as tissue-specific mechanisms of damage. As a consequence of its involvement in multiple stages of the immune-inflammatory response, MIF has the potential to be involved in the pathogenesis of a range of immunemediated inflammatory diseases affecting multiple organ systems. Diseases in which a role for MIF has been strongly validated include rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, atherosclerosis, asthma, inflammatory liver disease, and most recently systemic lupus erythematosus. Recent data have provided mechanisms of action for MIF which further support its suitability as a therapeutic target. Finally, MIF has a unique relationship with glucocorticoids, acting to counter-regulate their anti-inflammatory effects, such that MIF antagonist therapy may be a direct route to ‘steroid-sparing’. Methods of targeting MIF therapeutically have also emerged in recent years, based on the unique protein structure of MIF which affords opportunities for direct antagonism by small molecules, as well as by protein therapeutics such as monoclonal antibodies. Clinical trials of MIF antagonist therapies are likely before the end of the current decade.

Keywords: Macrophage migration inhibitory factor, inflammatory diseases, rheumatoid arthritis, systemic lupus erythematosus, atherosclerosis, cytokines, therapeutic target, small molecule antagonists