Tumour necrosis factor-α up-regulates macrophage migration inhibitory factor expression in endometrial stromal cells via the nuclear transcription factor NF-κB

BACKGROUND: A series of controlled changes including proliferation, secretion and menstrual shedding occur in the human endometrium during every normal menstrual cycle. Macrophage migration inhibitory factor (MIF), a multifunctional cytokine with numerous proinflammatory, immunomodulatory and angiogenic properties, appears to be expressed in the human endometrium and to follow a regulated cycle phase-dependent expression, but the mechanisms underlying endometrial MIF expression remain to be fully elucidated. METHODS AND RESULTS: Results from enzyme-linked immunosorbent assay (ELISA) demonstrated a significant dose- and time-dependent increase in MIF secretion by human endometrial cells in response to tumour necrosis factor-alpha (TNF-alpha) (0.1-100 ng/ml). This increase was also observed at the mRNA level as shown by reverse transcription (RT)-PCR. Curcumin (10(-8) mol/l), a known nuclear factor (NF)-kappa B inhibitor, inhibited the TNF-alpha-induced pI kappa B phosphorylation as shown by western blotting, NF-kappa B translocation into the nucleus as shown by electrophoretic mobility shift assay, and MIF synthesis and secretion as measured by ELISA and RT-PCR. The expression of a dominant-negative NF-kappa B inhibitor (I kappa B) significantly decreased the TNF-alpha-induced MIF promoter activity as analysed by transient cell transfection. CONCLUSIONS: These results indicate clearly that TNF-alpha up-regulates the expression of MIF in endometrial stromal cells. This took place possibly through NF-kappa B activation, and may play an important role in the physiology of the human endometrium.