Tumor necrosis factor-alpha regulates the gene expression of macrophage migration inhibitory factor through tyrosine...

Macrophage migration inhibitory factor (MIF) has been rediscovered as a proinflammatory cytokine, pituitary hormone, and glucocorticoid-induced immunoregulator. We have recently identified the expression of MIF in adipocytes and found that tumor necrosis factor (TNF)-alpha stimulates its secretion from 3T3-L1 adipocytes. Since adipocytes are regarded as a potential source of various biologically active substances, we examined in more detail the effect of TNF-alpha on MIF expression in 3T3-L1 adipocytes in the present study. We found that TNF-alpha induced MIF mRNA in dose- and time-dependent manners. After stimulation with TNF-alpha, the amount of intracellular MIF protein was unchanged or slightly decreased, concomitant with increased release of this protein into the extracellular space. This observation indicates that TNF-alpha stimulates MIF secretion from the constitutively expressed intracellular pool of 3T3-L1 adipocytes and promotes de novo synthesis of MIF. From evaluation of the mechanism of MIF gene expression, we found that tyrosine kinase inhibitors, either genistein or herbimycin A, suppressed the MIF mRNA induction by TNF-alpha. The results suggest the possibility that upregulation of MIF mRNA expression by TNF-alpha is mediated by a tyrosine kinase-dependent pathway. Taken together, the present observations shed light on the role of MIF in the metabolism of obesity and diabetes.