Trends in Microbiology
OpinionWhat a disorder: proinflammatory signaling pathways induced by Helicobacter pylori
Section snippets
Activation of immediate early factors by Helicobacter pylori colonization of the epithelium
Mucosal surfaces in mammals are protected by a first line of defence, termed innate immunity, which controls the resident microflora and acts to prevent microbial diseases [1]. The innate immune system senses specific components (e.g. flagellin, lipopolysaccharide or peptidoglycan) that are either present on the bacterial surface or are spontaneously released upon contact with target cells. The best-studied family of eukaryotic receptors recognizing microbial components comprises the Toll-like
One fact is clear: T4SS-dependent but CagA-independent activation of NF-κB
Early studies showed that IL-8 production in several epithelial cell lines was dependent on the presence of cagPAI; factors such as CagA, VacA or urease were excluded from IL-8 induction 19, 20, 21. This was in accordance with clinical investigations that assessed the relationship between IL-8 secretion and bacterial cagPAI status 3, 4. Furthermore, physical contact between Hp and epithelial cells was absolutely necessary and resulted in a rapid and CagA-independent activation of NF-κB 5, 11, 22
A subversive view of T4SS-dependent NF-κB activation: CagA-induced pathways
Because isogenic ΔcagA mutants often induce considerable amounts of IL-8, CagA was considered for long time to be dispensable for the induction of proinflammatory responses 20, 21, 22, 31. However, numerous recent reports demonstrated that injected and transfected CagA can induce NF-κB and IL-8 in AGS and other cell types. Transfection of CagA constructs resulted in the translocation of p65 into the nucleus, activation of the IL-8 promotor and subsequent IL-8 release [15]. Inhibitor studies and
T4SS-independent factors involved in NF-κB activation by Hp
In addition to pronounced T4SS-dependent activation of NF-κB, basal levels of inflammation are also induced by cagPAI-negative strains, indicating the presence of T4SS-independent pathways capable of stimulating NF-κB [4]. One of the cagPAI-independent factors appears to be urease, which is secreted to neutralize the pH around bacteria. Interestingly, urease was also found to coprecipitate with CD74, a surface receptor regulating intracellular transport and other functions [13]. Using urease
Hp activates AP-1 in a T4SS-dependent manner
There are only very few reports on how Hp activates AP-1, the other proinflammatory transcription factor. The first detailed pathway described is a cascade of the cellular stress-response kinases such as JNK, MAP kinase kinase 4 (MKK4), and PAK1, and small Rho GTPases, which contribute to the activation of proinflammatory cytokines/chemokines induced by Hp with a functional T4SS [43]. AP-1 activation was shown to be directly mediated by JNK (Figure 1e), which becomes phosphorylated by MKK4.
Hp-induced IL-8 secretion as sole read-out system
Finally, a large number of studies have investigated signaling pathways involved in IL-8 expression induced by Hp but did not address the requirement of NF-κB and/or AP-1. One proposed pathway represents a T4SS-dependent mechanism involving epidermal growth factor receptor (EGFR), H-Ras and MEK [47]. Other mechanisms were induced by transfected CagA constructs, and the use of inhibitors indicated a role of H-Ras and MEK [15] or Src and MEK [48] in IL-8 secretion. Another putative bacterial
Concluding remarks
The above discussed reports create a highly confusing situation of how Hp stimulates signaling cascades leading to activation of NF-κB and AP-1 in gastric epithelial cells. The reasons for the discrepancies are not fully clear, but probably stem from complexities associated with the different experimental approaches. One possible explanation for at least some contradictary data are ‘polar effects’ occurring during Hp mutagenesis 31, 43. Importantly, only two studies generated genetically
Acknowledgements
We apologize to all H. pylori researchers whose original work could not be cited due to length restriction of this article. The work was supported through the German Research Foundation by a grant to S.B. (Ba1671/8–1) and in part by the Collaborative Research Center 854 of the German Research Foundation by a grant to M.N.
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2022, Microbial PathogenesisCitation Excerpt :Virulent H. pylori strains have a cag-type IV secretion system (cag-T4SS), which induces the translocation of bacterial effector molecules (e.g., CagA, ADP-heptose and chromosomal DNA) into human host cells [3–5]. These translocated effector molecules triggered a strong pro-inflammatory response in host cells, including activation of nuclear factor κB (NF-κB) pathway and toll-like receptor-9 (TLR9) with consequences for secretion of the proinflammatory cytokines IL-1b and IL-8 [5,6]. Moreover, virulent H. pylori strains also have other virulence factors, such as vacuolating cytotoxin A (VacA) and adhesins (SabA and BabA).