Nuclear factor-kappaB and TNF-alpha mediate gastric ulceration induced by phorbol myristate acetate

Phorbol esters induce inflammation in rodents by activating protein kinase C. We determined whether nuclear factor-kappaB (NF-kappaB) and tumor necrosis factor-alpha (TNF-alpha) play role in the formation of gastric ulcer induced by phorbol-12-myristate-13-alphacetate (PMA) in rats. Subserosally injected PMA dose-dependently induced gastric mucosal ulcer. Activation of NF-kappaB in the gastric mucosa corresponding to the PMA injection sites was observed before the ulcers became obvious as assessed by an in situ fluorescence DNA binding assay and electrophoretic mobility shift assay. The NF-kappaB activation and subsequent ulcer formation were significantly inhibited by injection of pyrrolidine dithiocarbamate, proteasome inhibitor (MG132), or NF-kappaB decoy. Antibody against TNF-alpha significantly inhibited ulcer formation without attenuating NF-kappaB activation. These results suggest that both NF-kappaB activation followed by TNF-alpha release contribute to tissue damage in PMA-induced gastric ulcer formation.