Human esophageal epithelial cells play a key role in esophageal inflammation in response to acidic pH during gastroesophageal reflux disease, increasing secretion of IL-6 and IL-8. Mechanisms underlying IL-6 and IL-8 expression and secretion in esophageal epithelial cells following acid stimulation are not well characterized. We investigated the role of PKC, MAPK and NFB signaling pathways and transcriptional regulation of IL-6 and IL-8 expression in HET-1A cells exposed to acid. Exposure of HET-1A cells to pH 4.5 induced NFB activity, enhanced IL-6 and IL-8 secretion, mRNA and protein expression. Acid stimulation of HET-1A cells also resulted in activation of MAPKs and PKC ( and ). Curcumin, as well as inhibitors of NFB (SN-50), PKC (chelerythrine) and p44/42 MAPK (PD098059) inhibitors abolished the acid induced expression of IL-6 and IL-8. The JNK inhibitor SP600125 blocked expression/secretion of IL-6, but only partially attenuated IL-8 expression. The p38 MAPK inhibitor (SB203580) did not inhibit IL-6 expression, but exerted a stronger inhibitory effect on IL-8 expression. Together, these data demonstrate that 1) acid is a potent inducer of IL-6 and IL-8 production in HET-1A cells; 2) MAPKs and PKC signaling play a key regulatory role in acid mediated IL-6 and IL-8 expression via NFB activation; and 3) the anti-inflammatory plant compound curcumin inhibited esophageal activation in response to acid. Thus, IL-6 and IL-8 expression by acid may contribute to pathobiology of mucosal injury in GERD and inhibition of the NFB/proinflammatory cytokine pathways may emerge as important therapeutic targets for treatment of esophageal inflammation.