Macrophage migration inhibitory factor

Macrophage migration inhibitory factor (MIF or MMIF), also known as glycosylation-inhibiting factor (GIF), L-dopachrome isomerase, or phenylpyruvate tautomerase is a is_associated_with::protein that in humans is encoded by the MIF is_associated_with::gene. MIF is an important regulator of is_associated_with::innate immunity.

Bacterial is_associated_with::antigens stimulate is_associated_with::white blood cells to release MIF into the blood stream. The circulating MIF binds to is_associated_with::CD74 on other immune cells to trigger an acute immune response. Hence, MIF is classified as an inflammatory is_associated_with::cytokine. Furthermore is_associated_with::glucocorticoids also stimulate white blood cells to release MIF and hence MIF partially counteracts the inhibitory effects that glucocorticoids have on the immune system. Finally trauma activates the is_associated_with::anterior pituitary gland to release MIF.

Structure
Macrophage migration inhibitory factor assembles into a trimer composed of three identical subunits. Each of these monomers contain two antiparallel alpha helices and a four-stranded is_associated_with::beta sheet. The monomers surround a central channel with 3-fold is_associated_with::rotational symmetry.

Enzymatic activity
MIF contains two motifs with catalytic activity. The first is a 27 amino acid motif located at the is_associated_with::N-terminus functions as a is_associated_with::phenylpyruvate tautomerase that can catalyze the conversion of 2-carboxy-2,3-dihydroindole-5,6-quinone (is_associated_with::dopachrome) into 5,6-dihydroxyindole-2-carboxylic acid (is_associated_with::DHICA). MIF also contains a Cys-Ala-Leu-Cys catalytic site between residues 57 and 60 that appears to function as a is_associated_with::disulfide is_associated_with::reductase.

Function
This gene encodes a is_associated_with::lymphokine involved in is_associated_with::cell-mediated immunity, immunoregulation, and is_associated_with::inflammation. MIF plays a role in the regulation of is_associated_with::macrophage function in host defense through the suppression of anti-inflammatory effects of is_associated_with::glucocorticoids. This lymphokine and the JAB1 protein form a complex in the is_associated_with::cytosol near the peripheral plasma membrane, which may indicate a role in is_associated_with::integrin signaling pathways.

Mechanism of action
MIF binds to is_associated_with::CD74, inducing its is_associated_with::phosphorylation and the recruitment of is_associated_with::CD44 which then activates is_associated_with::non-receptor tyrosine kinases, leading ultimately to is_associated_with::extracellular signal-regulated kinase phosphorylation.

Interactions
Macrophage migration inhibitory factor has been reported to interact with:
 * is_associated_with::BNIPL,
 * is_associated_with::CD74,
 * COPS5,
 * is_associated_with::CXCR4,  and
 * RPS19.

Clinical significance
MIF is an inflammatory mediator associated with is_associated_with::rheumatoid arthritis (RA) severity.

It has also been shown to induce changes in the heart during is_associated_with::sepsis.

Additionally, evidence suggests that there is a correlation between MIF production and metastatic potential in is_associated_with::colorectal cancer.