Chemical Synthesis of Helicobacter pylori Lipopolysaccharide Partial Structures and their Selective Proinflammatory Responses

• Published in: Chemistry : a European journal 2011-12, Vol.17 (51), p.14464-14474
• Main Authors: Shimoyama, Atsushi, Saeki, Akinori, Tanimura, Natsuko, Tsutsui, Hiroko, Miyake, Kensuke, Suda, Yasuo, Fujimoto, Yukari, Fukase, Koichi
• Format: Article
• Language: English
• Subjects: Activation; Atherosclerosis; Bacteria; Chemistry; Cytokines; Cytokines - drug effects; Cytokines - immunology; Escherichia coli - chemistry; Escherichia coli - immunology; Ethanolamines - chemistry; Gastritis - immunology; Gastritis - microbiology; glycolipids; Glycosylation; Helicobacter pylori; Helicobacter pylori - chemistry; Helicobacter pylori - drug effects; Helicobacter pylori - immunology; Humans; immunochemistry; inflammation; Interleukin-12 - immunology; Interleukin-6 - immunology; Interleukin-8 - immunology; Lipid A - chemical synthesis; Lipid A - chemistry; Lipid A - immunology; Lipopolysaccharides - chemical synthesis; Lipopolysaccharides - chemistry; Lipopolysaccharides - immunology; Microfluidics; NF-kappa B - drug effects; Peptic ulcers; Stimulation; Structure-Activity Relationship; synthetic methods; Ulcers
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201003581

Helicobacter pylori is a common cause of gastroduodenal inflammatory diseases such as chronic gastritis and peptic ulcers and also an important factor in gastric carcinogenesis. Recent reports have demonstrated that bacterial inflammatory processes, such as stimulation with H. pylori lipopolysaccharide (LPS), initiate atherosclerosis. To establish the structures responsible for the inflammatory response of H. pylori LPS, we synthesized various kinds of lipid A structures (i.e., triacylated lipid A and Kdo‐lipid A compounds), with or without the ethanolamine group at the 1‐phosphate moiety, by a new divergent synthetic route. Stereoselective α‐glycosylation of Kdo N‐phenyltrifluoroacetimidate was achieved by use of microfluidic methods. None of the lipid A and Kdo‐lipid A compounds were a strong inducer of IL‐1β, IL‐6, or IL‐8, suggesting that H. pylori LPS is unable to induce acute inflammation. In fact, the lipid A and Kdo‐lipid A compounds showed antagonistic activity against cytokine induction by E. coli LPS, except for the lipid A compound with the ethanolamine group, which showed very weak agonistic activity. On the other hand, these H. pylori LPS partial structures showed potent IL‐18‐ and IL‐12‐inducing activities. IL‐18 has been shown to correlate with chronic inflammation, so H. pylori LPS might be implicated in the chronic inflammatory responses induced by H. pylori. These results also indicated that H. pylori LPS can modulate the immune response: NF‐κB activation through hTLR4/MD‐2 was suppressed, whereas production of IL‐18 and IL‐12 was promoted. Inflammatory materials: Lipopolysaccharide (LPS) partial structures of Helicobacter pylori, including triacylated lipid A and Kdo‐lipid A compounds, with or without the ethanolamine group at the 1‐phosphate, were synthesized (see scheme). Stereoselective α‐glycosylation of Kdo n‐phenyltrifluoroacetimidate was achieved by microfluidic methods. Cytokine induction assays suggested a link between H. pylori LPS and chronic inflammation and atherosclerosis.