HUMAN CIRCULATING EOSINOPHILS SECRETE MACROPHAGE-MIGRATION INHIBITORYFACTOR (MIF) - POTENTIAL ROLE IN ASTHMA

Macrophage migration inhibitory factor (MIF) is a potent proinflammato ry mediator that has been shown to potentiate lethal endotoxemia and t o play a potentially important regulatory role in human acute respirat ory distress syndrome (ARDS), We have investigated whether eosinophils are an important source of MIF and whether MIF may be involved in the pathophysiology of asthma, Unstimulated human circulating eosinophils were found to contain preformed MIF. Stimulation of human eosinophils with phorbol myristate acetate in vitro yielded significant release o f MIF protein. For example, eosinophils stimulated with phorbol myrist ate acetate (100 nM, 8 h, 37 degrees C) released 1,539 +/- 435 pg/10(6 ) cells of MTF, whereas unstimulated cells released barely detectable levels (< 142 pg/10(6) cells, mean +/- SEM, n = 8), This stimulated re lease was shown to be (a) concentration- and time-dependent, (b) parti ally blocked by the protein synthesis inhibitor cycloheximide, and (c) significantly inhibited by the protein kinase C inhibitor Ro-31,8220. In addition, we show that the physiological stimuli C5a and IL-5 also cause significant MIF release. Furthermore, bronchoalveolar lavage fl uid obtained from asthmatic patients contains significantly elevated l evels of MIF as compared to nonatopic normal volunteers (asthmatic, 79 7.5 +/- 92 pg/ml; controls, 274 +/- 91 pg/ml). These results highlight the potential importance of MIF in asthma and other eosinophil-depend ent inflammatory disorders.