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

Abstract

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.

Inflammation, Immunity, and Vaccines for Helicobacter pylori Infection

“…In another suggested mechanism of immune evasion, H. pylori was shown to inhibit macrophage release of nitric oxide in response to H. pylori LPS in a mouse model of infection (2). H. pylori LPS was also shown to suppress TLR-4 signaling, but enhance IL-12 and IL-18 production (3), which was suggested to be linked to the chronic inflammation commonly seen during infection. In further support for the role of H. pylori LPS signaling through TLR-2 instead of TLR-4, one group demonstrated that upon TLR-2 activation by LPS derived from H. pylori inhibited the TRIB3 protein, which controls TLR-2-mediated NF-κB signaling, thus leading to increased NF-κB signaling (4).…”

“…A further role TLR-2 was shown in addition to TLR-5 expression by H. pylori on THP-1 monocytic leukemia cells resulted in a shift from cagPAI-dependent to cagPAI- independent signalling leading to the secretion of IL-8 and TNF-α (5). In NK cells, TLR-2 was shown to be activated by H. pylori lipoprotein HpaA, leading to IFN-γ production in an IL-12 dependent manner (3, 6). In further analysis of TLR-2 activation by H. pylori , urease was shown to activate TLR-2 on B cells, inducing autoantibodies and suggesting a link to autoimmune disorders (7).…”

Fas-associated factor 1 inhibits tumor growth by suppressing Helicobacter pylori-induced activation of NF-κB signaling in human gastric carcinoma

“…Our laboratory has shown that among gastric cancer patients, FAF1 mRNA levels are lower in tissues positive for H. pylori than in tissues negative for H. pylori [7]. H. pylori may increase risk of gastric cancer in part by activating NF-κB signaling [10, 11], leading to secretion of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1β), interleukin-6 (IL-6) and interleukin-8 (IL-8). Therefore we wondered whether FAF1 may be affected by NF-κB signaling.…”

Stereoselective Synthesis of α‐3‐Deoxy‐D‐manno‐oct‐2‐ulosonic Acid (α‐Kdo) Glycosides Using 5,7‐O‐Di‐tert‐butylsilylene‐Protected Kdo Ethyl Thioglycoside Donors

“…at À78 to À50 8 8CinCH 2 Cl 2 ( Table 1). Gratifyingly,the thioglycosides 1c-e,b earing a5 ,7-O-DTBS group,e xhibited strong stereocontrol during the condensations with 2 and complete aanomeric selectivity was obtained for the products 3ce (entries [3][4][5]. [4e, 11] For the a-anomer, the 3 J C-1/H-3ax value is 1.0 Hz, while,for the banomer,t he 3 J C-1/H-3ax is 5.0-6.0 Hz.…”