IL-1 modulation of H,K-ATPase -subunit gene transcription in Helicobacter pylori infection

Saha A, Hammond CE, Gooz M, Smolka AJ. IL-1 modulation of H,K-ATPase -subunit gene transcription in Helicobacter pylori infection. Am J Physiol Gastrointest Liver Physiol 292: G1055–G1061, 2007. First published January 4, 2007; doi:10.1152/ajpgi.00338.2006.—Helicobacter pylori infection of the 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 (AGS) cells were transfected with promoter-reporter constructs containing human HK 5 -flanking sequence deletions. IL-1 (10 ng/ml) had no effect on the transcriptional activity of six progressively shorter deletion constructs of the HK promoter (HK 2179– HK 340) and significantly stimulated the activity of HK 206, HK 177, HK 165, and HK 102 deletion constructs (80%, 100%, 46%, and 35%, respectively). H. pylori inhibited the transcriptional activity of HK 2179, HK 206, HK 177, and HK 165; IL-1 relieved the H. pylori inhibition of HK 2179 and HK 206 activity but not HK 177 and HK 165 activity. AGS cell pretreatment with a MEK1/2 inhibitor prevented the 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. pyloriconditioned 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 upregulation of HK transcription is affected by an ERK1/2 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 .