Pyrrolidinedithiocarbamate inhibits NF-kappaB activation and IL-8 production in intestinal epithelial cells

During inflammatory bowel disease and intestinal ischemia, epithelial cells of the gut mucosa produce various inflammatory mediators, including the chemokine interleukin (IL-8). This IL-8 produced by intestinal epithelial cells has recently been implicated as a contributory factor to the deleterious inflammatory process resulting in colitis during inflammatory bowel disease or multiple organ failure following shock and trauma. Recent evidence suggests that the transcription factor nuclear factor kappaB (NF-kappaB) is a central regulator of IL-8 gene expression. In the present paper we investigated the effect of pharmacological inhibition of NF-kappaB with pyrrolidinedithiocarbamate (PDTC) on IL-1beta-induced IL-8 production by the human intestinal epithelial cell line HT-29. Pretreatment of cells with PDTC (3-1000 microM) dose-dependently attenuated IL-8 production. Furthermore, PDTC (100 microM) suppressed the accumulation of IL-8 mRNA. PDTC inhibited the activation of NF-kappaB, because PDTC suppressed both NF-kappaB DNA binding and NF-kappaB-dependent transcriptional activity. Taken together, our data demonstrate that NF-kappaB inhibition with PDTC decreases IL-8 production by intestinal epithelial cells.