Macrophage migration inhibitory factor: controller of systemic inflammation

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.


Introduction
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 [1] 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.

Macrophage migration inhibitory factor
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, cyclooxygenase-2, nitric oxide, and products of the arachidonic acid pathway [2].
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 [3]. 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 [1].

Adaptive immune system: T-helper-1/2 cells
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 [4]. The Th1 pathway is associated with induction of cellular

Macrophage migration inhibitory factor: controller of systemic inflammation
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.

Integration of macrophage migration inhibitory factor and the adaptive immune system
The pathways described in Figure 1 may elucidate a mechanism of MIF-mediated SIRS as a consequence of cardiovascular surgery using cardiopulmonary bypass. The initial stressors induce pituitary secretion of MIF and ACTH. ACTHstimulated glucocorticoids and/or immunologic mediators may induce release of MIF by Th2 cells [5]. Most importantly, MIF counter-regulates the inhibitory effects of glucocorticoids on proinflammatory cytokines, thereby enhancing the cytokine-mediated SIRS. An alternate pathway is also probable because LPS has been shown to increase during cardiopulmonary bypass, which may directly induce MIF secretion by immune cells [6]. MIF thereby stimulates Th1 immune activity and induces proinflammatory cytokines and amplification of macrophage function. Within the context of inflammatory responses, the Th1 pathway controls macrophage activity, which is the main source of proinflammatory cytokines. These proinflammatory cytokines are highly pleiotropic and stimulate neutrophil and macrophage function and, in addition, induce production of acute phase proteins, fever, and cachexia. The Th2 pathway counterbalances the Th1 pathway mainly via IL-10 and to a lesser extent IL-4. IL-10 is a potent endogenous immunosuppressant cytokine that inhibits Th1 proinflammatory cytokines [7]. The principle Th1 cytokine, namely IFN-γ, is a potent stimulator of monocyte chemoattractant protein-1, which further stimulates macrophage function. The Th2 cytokine IL-13 can counterbalance this pathway through inhibition of monocyte chemoattractant protein-1. CD40 and CD40 ligand are integral membrane proteins that function to mediate interactions between cells and antigen-presenting cells. The release of sCD40 is therefore a marker of immune activation.

Conclusion
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 [8] 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][10][11][12], which also would affect the balance of the Th1/Th2 response.