Fig. 1

MIF function and signaling. MIF fulfills its biological functions through membrane receptors and via binding to intracellular molecules. MIF’s binding to membrane receptor CD74 recruits CD44 and leads to activation of Src/MAPK signaling. MIF via CXCR2/4 activates PI3K/Akt downstream signaling and induces cell migration. Sustained activation of ERK1/2 phosphorylation is mediated by JUN activation domain binding protein-1 (JAB1) and leads to cytoplasmic phospholipase A2 (cPLA2) activity (blocked by glucocorticoids) and further to arachidonate/prostaglandin production. MIF production can be stimulated via TLRs by e.g., LPS stimulation. MIF regulates innate immune responses through modulation of TLR4. In response to LPS and Gram-negative bacteria MIF upregulates TLR-4 expression and in consequence induces the production of pro-inflammatory cytokines. MIF overrules glucocorticoid effects such as the nuclear factor-κB (NF-κB) inhibitor IκB which downregulates inflammatory responses. MIF via p53 inhibits activation-induced apoptosis, increase cellular survival and proliferation. MIF’s functions include: 1. stimulation of proinflammatory and co-stimulatory factors; 2. activation of adhesion molecules; 3. increase of cell trafficking to the sites of inflammation; 4. increase of cell proliferation and survival and inhibition of apoptosis