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Neisseria gonorrhoeaeexpress opacity-associated (Opa) protein adhesins that mediate binding to various members of the carcinoembryonic antigen-related cellular adhesion molecule (CEACAM; previously CD66) receptor family. Although human umbilical vein endothelial cells express little CEACAM receptor in vitro, we found neisserial infection to induce expression of CEACAM1, CEACAM1-3L, and CECAM1-4L splice variants. This mediates an increased Opa52-dependent binding of gonococci by these cells. The induced receptor expression did not require bacterial Opa expression, but it was more rapid with adherent bacteria. Because the time course of induction was similar to that seen for induced proinflammatory cytokines, we tested whether CEACAM1 expression could be controlled by a similar mechanism. Gonococcal infection activated a nuclear factor-κB (NF-κB) heterodimer consisting of p50 and p65, and inhibitors that prevent the nuclear translocation of activated NF-κB complex inhibited CEACAM1 transcript expression. Each of these effects could be mimicked by using culture filtrates or purified lipopolysaccharide instead of intact bacteria. Together, our results support a model whereby the outer membrane “blebs” that are actively released by gonococci trigger a Toll-like receptor-4-dependent activation of NF-κB, which up-regulates the expression of CEACAM1 to allow Opa52-mediated neisserial binding. The regulation of CEACAM1 expression by NF-κB also implies a broader role for this receptor in the general inflammatory response to infection.

Helicobacter pyloriinitiates an inflammatory response and gastric diseases, which are more common in patients infected with H. pyloristrains carrying the pathogenicity island, by colonizing the gastric epithelium. In the present study we investigated the mechanism of prostaglandin E2(PGE2) synthesis in response to H. pyloriinfection. We demonstrate that H. pyloriinduces the synthesis of PGE2via release of arachidonic acid predominately from phosphatidylinositol. In contrast to H. pyloriwild type, an isogenic H. pyloristrain with a mutation in the pathogenicity island exerts only weak arachidonic acid and PGE2synthesis. The H. pylori-induced arachidonic acid release was abolished by phospholipase A2(PLA2) inhibitors and by pertussis toxin (affects the activity of Gαi/Gαo). The role of phospholipase C, diacylglycerol lipase, or phospholipase D was excluded by using specific inhibitors. An inhibitor of the stress-activated p38 kinase (SB202190), but neither inhibitors of protein kinase C nor an inhibitor of the extracellular-regulated kinase pathway (PD98059), decreased the H. pylori-induced arachidonic acid release.H. pylori-induced phosphorylation of p38 kinase and cytosolic PLA2was blocked by SB202190. These results indicate that H. pyloriinduces the release of PGE2from epithelial cells by cytosolic PLA2activation via Gαi/Gαoproteins and the p38 kinase pathway.

Helicobacter pyloriinfection of the gastric mucosa is accompanied by an activated histamine metabolism. Histamine plays a central role in the regulation of gastric acid secretion and is involved in the pathogenesis of gastroduodenal ulcerations. Histidine decarboxylase (HDC) is the rate-limiting enzyme for histamine production, and its activity is regulated through transcriptional mechanisms. The present study investigated the effect of H. pyloriinfection on the transcriptional activity of the human HDC (hHDC) promoter in a gastric epithelial cell line (AGS) and analyzed the underlying molecular mechanisms. Our studies demonstrate that H. pyloriinfection potently transactivated the hHDC promoter. The H. pylori-responsive element of the hHDC gene was mapped to the sequence +1 to +27 base pairs, which shows no homology to known cis-acting elements and also functions as a gastrin-responsive element. H. pyloriregulates the activity of this element via a Raf-1/MEK/ERK pathway, which was activated in a Ras-independent manner. Furthermore, we found that H. pylori-induced transactivation of the hHDC promoter was independent of the cagpathogenicity island and the vacuolating cytotoxin A gene and therefore may be exerted through (a) new virulence factor(s). A better understanding of H. pylori-directed hHDC transcription can provide novel insights into the molecular mechanisms of H. pylori-dependent gene regulation in gastric epithelial cells and may lead to new therapeutic approaches.

Helicobacter pyloriinteracts with the apical membrane of the gastric epithelium and induces a number of proinflammatory cytokines/chemokines. The subsequent infiltration of macrophages and granulocytes into the mucosa leads to gastric inflammation accompanied by epithelial degeneration. Gastric diseases,e.g.peptic ulcer or gastric adenocarcinoma, are more common among people infected with H. pyloristrains producing VacA (vacuolating cytotoxin A) and possessing acag(cytotoxin-associated antigen A) pathogenicity island. For the induction of the cytokine/chemokine genes in response toH. pylori,we studied the signaling leading to the nuclear activation of the early response transcription factor activator protein 1 (AP-1). We found that H. pyloristrains carrying the pathogenicity island induce activation of AP-1 and nuclear factor κB. In contrast to the wild type or an isogenic strain without thevacAgene, isogenic H. pyloristrains with mutations in certain caggenes revealed only weak AP-1 and nuclear factor κB activation. In respect to the molecular components that direct AP-1 activity, our results indicate a cascade of the cellular stress response kinases c-Jun N-terminal kinase, MAP kinase kinase 4, and p21-activated kinase, and small Rho-GTPases including Rac1 and Cdc42, which contributes to the activation of proinflammatory cytokines/chemokines induced by H. pyloriencoding thecagpathogenicity island.