Intracellular action of the cytokine MIF to modulate AP-1 activity and thecell cycle through Jab1

Cytokines are multifunctional mediators that classically modulate immune ac tivity by receptor-mediated pathways. Macrophage migration inhibitory facto r (MIF) is a cytokine that has a critical role in several inflammatory cond itions(1-3) but that also has endocrine(4,5) and enzymatic functions(6,7). The molecular targets of MIF action have so far remained unclear. Here we s how that MIF specifically interacts with an intracellular protein, Jab1, wh ich is a coactivator of AP-1 transcription(8,9) that also promotes degradat ion of the cyclin-dependent kinase inhibitor p27(Kip1) (ref. 10). MIF coloc alizes with Jab1 in the cytosol, and both endogenous and exogenously added MIF following endocytosis bind Jab1. MIF inhibits Jab1- and stimulus-enhanc ed AP-1 activity, but does not interfere with the induction of the transcri ption factor NF kappaB. Jab1 activates c-Jun amino-terminal kinase (JNK) ac tivity and enhances endogenous phospho-c-Jun levels, and MIF inhibits these effects. MIF also antagonizes Jab1-dependent cell-cycle regulation by incr easing p27(Kip1) expression through stabilization of p27(Kip1) protein. Con sequently, Jab1-mediated rescue of fibroblasts from growth arrest is blocke d by MIF. Amino acids 50-65 and Cys 60 of MIF are important for Jab1 bindin g and modulation. We conclude that MIF may act broadly to negatively regula te Jab1-controlled pathways and that the MIF-Jab1 interaction may provide a molecular basis for key activities of MIF.