Macrophage migration inhibitory factor: controller of systemic inflammation
© BioMed Central Ltd 2006
Published: 6 April 2006
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© BioMed Central Ltd 2006
Published: 6 April 2006
Macrophage migration inhibitory factor (MIF) is a cytokine that is secreted by the anterior pituitary and immune cells in response to surgical stress, injury, and sepsis. This cytokine appears to be a critical regulator of the inflammatory pathways, leading to systemic inflammatory response syndrome and subsequent multiple organ dysfunction syndrome. This report provides an integrated scheme describing the manner by which MIF controls the neurohormonal response and the adaptive immune system, namely the T-helper (Th)1 and Th2 lymphocytes, which results in the release of pro-inflammatory cytokines and the anti-inflammatory cytokine interleukin-10. The development of systemic inflammatory response syndrome and subsequent development of multiple organ dysfunction syndrome appear to be related to MIF levels and the balance of Th1 and Th2 function.
For the survival for all living creatures, an appropriate and balanced immune response to invading micro-organisms is essential. However, in the case of cardiovascular surgery, resembling sepsis and injury, an exaggerated inflammatory response, described as systemic inflammatory response syndrome (SIRS), may result in multiple organ dysfunction syndrome (MODS). The report by de Mendonça-Filho and coworkers  included in this issue of Critical Care demonstrates that a SIRS cytokine, namely macrophage migration inhibitory factor (MIF), correlates directly with MODS following open heart surgery and Sequential Organ Failure Assessment score.
MIF is a distinctive cytokine because it is secreted by the immune cells and the anterior pituitary gland. T cells appear to be the main immune source of MIF, but MIF is also expressed by most other immune cell types, including those that facilitate acute inflammatory responses. Moreover, adrenocorticotropic hormone (ACTH), which increases secondary to surgical stress, in turn induces glucocorticoid hormones. Glucocorticoid hormones induce immune cell secretion of MIF. Third, proinflammatory cytokines and/or binding of the bacterial endotoxin lipopolysaccharide (LPS) also induce MIF by immune cells. The secreted MIF binds to its receptor CD74, which is expressed mainly by major histocompatibility complex class II positive cells, namely antigen presenting cells such as macrophages, lymphocytes, dendritic cells, and endothelial cells. MIF thereby stimulates the expression and secretion of the proinflammatory cytokines tumor necrosis factor-α, IFN-γ, IL-1β, IL-6, and IL-8, in addition to macrophage inflammatory protein-2, cyclo-oxygenase-2, nitric oxide, and products of the arachidonic acid pathway .
The importance of MIF as a key mediator of systemic inflammatory responses is supported by the observation that deletion of the MIF gene or neutralization of the protein induces protection from LPS-induced shock . Therefore, the overall activity of MIF results in enhancement of the proinflammatory cytokine pathway related to SIRS, which has been directly associated with cardiovascular surgery, sepsis, and injury-mediated MODS .
There are two general pathways in the adaptive immune system that are related to the expressed and secreted cytokine profiles. The cytokine profile that has been used to describe subtypes of Th (CD4+) lymphocytes is Th1 and Th2; Th1 cells produce IL-2, IL-12, IFN-γ and tumor necrosis factor-α/β, and Th2 cells produce IL-4, IL-5, IL-10 and IL-13 . The Th1 pathway is associated with induction of cellular immunity, namely activation of CD8+ lymphocyte and macrophage functions. The Th2 cytokines generally support the humoral mediated responses related to B-lymphocyte function and immunoglobulin isotype.
In summary, the development of SIRS and subsequent evolution of MODS appears to be related to the balance of Th1 and Th2 function. Over-expression of MIF favors Th1 and thereby results in an exaggerated SIRS condition. A dominant Th2 function leading to high expression of IL-10 should logically temper the Th1 pathway and reduce the magnitude of SIRS and resulting MODS. However, a report suggesting that genotypic variants in IL-10 predispose individuals to SIRS  is counter to the above logic, but it emphasizes the involvement of an additional parameter, namely the patient cytokine genotype. Therefore, the genotype of the patient also appears to be a key predictive marker of response to surgical, injury, and sepsis-mediated SIRS [9–12], which also would affect the balance of the Th1/Th2 response.
macrophage migration inhibitory factor
multiple organ dysfunction syndrome
systemic inflammatory response syndrome
This study was supported by NIH R01 HL079206-01, James and Linda Lee Heart Failure Research Award, and Steinbronn Heart Failure Research Award to DFL.