Induction of MIF expression by oxidized LDL via activation of NF-kappaB in vascular smooth muscle cells.

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine playing important roles in atherosclerosis. MIF gene deficiency and neutralizing antibodies against MIF have been reported to exert anti-atherosclerotic effects in various animal models. However, the mechanism by which MIF is induced in atherosclerotic lesions remains unclear. In the present studies, we cloned a 540bp full-length rabbit MIF cDNA by screening a rabbit uterine library. The cDNA contains a 348bp open-reading frame which encodes a deduced 115-amino acid polypeptide with approximately 90% similarity to human and mouse homologs. Constitutive MIF mRNA expression was detected in most rabbit tissues including aortas. The expression of MIF obviously abounded in vascular smooth muscle cells (VSMCs) of the atherosclerotic plaques. In cultured VSMCs, MIF expression was significantly induced by a pro-atherogenic factor, oxidized low-density lipoprotein (oxLDL). Promoter analysis showed there were two NF-kappaB binding sites in the MIF proximal promoter region. Deletion or mutation of the two sites abolished oxLDL-enhanced MIF promoter activity. Moreover, the induction of MIF by oxLDL can be blocked by IkappaB-alpha overexpression. Taken together, our results revealed that MIF expression can be induced by oxLDL in VSMCs via a NF-kappaB dependent manner, which may contribute to the pathogenesis of atherosclerosis.