MIF Action Through Endocytic Pathway
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MIF Action Through Endocytic Pathway
The cytokine MIF(Macrophage Migration Inhibitory Factor) is an integral mediator of the innate immune system. Monocytes and macrophages constitutively express large amounts of MIF, which is rapidly released after exposure to bacterial toxins and cytokines. MIF exerts potent proinflammatory activities and is an important cytokine of septic shock. MIF regulates innate immune responses to endotoxin and gram-negative bacteria by modulating the expression of TLR4 (Toll-Like Receptor-4), the signal-transducing molecule of the LPS (Lipopolysaccharide) receptor complex (Ref.1).

Cells may take up MIF by endocytosis — a process by which a cells outer membrane engulfs extracellular substances (often in a nonspecific way) and imports them into the cell in membrane-bound vesicles or they can be transported to inside of the cell through receptor mediated signaling. The endocytosis can only be occurred when there is high concentration of MIF in the extracellular region is very high. MIF could then meet up with JAB1 in the cytoplasm. MIF interacts inside cells with an activator of gene expression, JAB1 (Jun Activation Domain-Binding Protein) and deactivates it. This protein usually induces both the phosphorylation of c-Jun, a protein involved in inducing cell growth, and the activity of AP-1, a transcription factor that activates the expression of pro-inflammatory genes (Ref.2).

JAB1 also binds to and promotes the degradation of p27(KIP1), a protein that halts the cell-division cycle. By doing this, JAB1 can rescue serum-starved fibroblasts from growth arrest. MIF, however, inhibits JAB1, allowing levels of p27(KIP1) to rise; when overexpressed, MIF reduces the growth-promoting effects of JAB1 on fibroblast cells. MIF-mediated effects mirror p27(KIP1) -mediated growth arrest and that this occurs through inhibition of Jab1-dependent degradation of p27(KIP1) (Ref.3).

MIF is also involved in the sustained activation of cell-growth-promoting enzymes such as ERK1 (Extracellular Signal-Regulated Kinase-1) /ERK2 (Extracellular Signal-Regulated Kinase-2), in promoting the growth of new blood vessels to nourish tumors, and in regulating antitumor T cells.