H. pylori infection of human gastric body induces hypochlorhydria by perturbing acid secretion. H. pylori inhibits parietal cell H,K-ATPase subunit (HK) gene and protein expression, providing a mechanistic basis for clinical hypochlorhydria. Given that H. pylori infection increases gastric mucosal IL-1, an acid secretory inhibitor, we investigated the role of IL-1 in H. pylori-mediated inhibition of HK transcription. Human gastric adenocarcinoma cells (AGS) were transfected with promoter-reporter constructs containing human HK 5'-flanking sequence deletions. IL-1 (10 ng/ml) had no effect on transcriptional activity of six progressively-shorter deletion constructs of HK promoter (HK2179-HK340) and significantly stimulated the activity of the HK206, HK177, HK165 and HK102 deletion constructs (80%, 100%, 46% and 35% respectively). H. pylori inhibited transcriptional activity of HK2179, HK206, HK177 and HK165; IL1- relieved H. pylori inhibition of HK2179 and HK206 activity but not HK177 and HK165. AGS cell pre-treatment with MEK-1/2 inhibitor prevented IL-1-mediated stimulation, but p38 and JNK pathway inhibitors did not. IL-1 mRNA levels in AGS cells were low and unaffected by H. pylori, and ELISAs of H. pylori-conditioned AGS culture media showed no measurable IL-1 secretion. These data indicate that an IL-1-dependent cis-response element lies downstream of -206 nt in the HK promoter, and that IL-1-mediated up-regulation of HK transcription is effected by an ERK-1/2 kinase signal pathway. We conclude that an IL-1-responsive HK cis element positively regulates HK gene transcription in shortened deletion constructs, and that H. pylori-induced inhibition of HK transcription is not mediated by IL-1.