Nordihydroguaiaretic acid blocks secretory and endocytic pathways in humandendritic cells

Nordihydroguaiaretic acid (NDGA), an antioxidant and inhibitor of the lipox ygenase arm of the arachidonic acid metabolism, was recently demonstrated t o inhibit transport of secretory proteins to the Golgi complex. We have inv estigated the effects of NDGA on the secretory and endocytic activity of cu ltured human blood dendritic cells (DC), Treatment with NDGA strongly dimin ished cytokine secretion by DC. Moreover, NDGA reduced in a dose- and time- dependent fashion fluid phase as web as receptor-mediated endocytosis in DC . Zileuton and MK-886, specific inhibitors of 5-lipoxygenase and 5-lipoxyge nase-activating protein, respectively, had no effect. Likewise, N-acetyl-L- cysteine, a thiol antioxidant precursor of glutathione, did not affect DC f unction. Finally, serum remarkably protected the cells from the inhibitory effects of NDGA, Our data demonstrate that NDGA not only disrupts vesicular transport along the secretory route but is also a potent inhibitor of the endocytic pathways in human DC and that NDGA has inhibitory properties diff erent from those described.