Sustained mitogen-activated protein kinase (MAPK) and cytoplasmic phospholipase A2 activation by macrophage migration inhibitory factor (MIF) - Regulatory role in cell proliferation and glucocorticoid action

Macrophage migration inhibitory factor (MIF) is an important pro-inflammato ry mediator with the unique ability to counter-regulate the inhibitory effe cts of glucocorticoids on immune cell activation. MIF is released from cell s in response to glucocorticoids,certain pro-inflammatory stimuli, and mito gens and acts to regulate glucocorticoid action on the ensuing inflammatory response. To gain insight into the molecular mechanism of MIF action, we h ave examined the role of MIF in the proliferation and intracellular signali ng events of the well characterized, NIH/3T3 fibroblast cell line. Both end ogenously secreted and exogenously added MIFs stimulate the proliferation o f NIH/3T3 cells, and this response is associated with the activation of the p44/p42 extracellular signal-regulated (ERK) mitogen-activated protein kin ases (MAP). The MIF-induced activation of these kinases was sustained for a period of at least 24 h and was dependent upon protein kinase A activity. We further show that MIF regulates cytosolic phospholipase Az activity via a protein kinase A and ERK dependent pathway and that the glucocorticoid su ppression of cytokine-induced cytoplasmic phospholipase A2 activity and ara chidonic acid release can be reversed by the addition of recombinant MIF. T hese studies indicate that the sustained activation of p44/p42 MAP kinase a nd subsequent arachidonate release by cytoplasmic phospholipase A2 are impo rtant features of the immunoregulatory and intracellular signaling events i nitiated by MIF and provide the first insight into the mechanisms that unde rlie the pro-proliferative and inflammatory properties of this mediator.