Ca²⁺/calmodulin-dependent kinase II contributes to inhibitor of nuclear factor-kappa B kinase complex activation inHelicobacter pyloriinfection

Abstract

Helicobacter pylori, a class I carcinogen, induces a proinflammatory response by activating the transcription factor nuclear factor-kappa B (NF-jB) in gastric epithelial cells. This inflammatory condition could lead to chronic gastritis, which is epidemiologically and biologically linked to the development of gastric cancer. So far, there exists no clear knowledge on how H. pylori induces the NF-jB-mediated inflammatory response. In our study, we investigated the role of Ca 21 /calmodulindependent kinase II (CAMKII), calmodulin, protein kinases C (PKCs) and the CARMA3-Bcl10-MALT1 (CBM) complex in conjunction with H. pylori-induced activation of NF-jB via the inhibitor of nuclear factor-kappa B kinase (IKK) complex. We use specific inhibitors and/or RNA interference to assess the contribution of these components. Our results show that CAMKII and calmodulin contribute to IKK complex activation and thus to the induction of NF-jB in response to H. pylori infection, but not in response to TNF-a. Thus, our findings are specific for H. pylori infected cells. Neither the PKCs a, d, h, nor the CBM complex itself is involved in the activation of NF-jB by H. pylori. The contribution of CAMKII and calmodulin, but not PKCs/CBM to the induction of an inflammatory response by H. pylori infection augment the understanding of the molecular mechanism involved and provide potential new disease markers for the diagnosis of gastric inflammatory diseases including gastric cancer.

Protein methionine oxidation augments reperfusion injury in acute ischemic stroke

“…These observations are consistent with previous work showing that CaMKII can promote NF-κB activation in gastric cancer (49), small-cell lung cancer (50), lymphoblastoid cells (51), and gastric epithelial cells (52). CaMKII also has been shown to contribute to NF-κB–dependent myocardial hypertrophy, myocardial ischemia/reperfusion injury, and mortality following myocardial infarction in animal models (25, 27).…”

NF‐κB Signaling in Gastric Cancer

“…c-Src kinase binds transiently to IKKβ and phosphorylates IKKβ, and contributes at least in part to NF-κB activation in response to H. pylori infection [59]. Protein kinases Cα, δ, θ and the CARMA3-Bcl10-MALT1 complex are supposedly not involved in H. pylori -induced activation of NF-κB [60]. However, following long infection with H. pylori , many factors could be transcriptionally regulated with contributory roles in NF-κB activation [61].…”

“…S100A8/9 is able to activate NF-κB and mitogen-activated protein kinase (MAPK) p38 leading to MMP-2 and MMP-12 expression and increase thereby migration and invasion of gastric cancer cells [75]. Interestingly, TNF does not directly regulate calcium/calmodulin signaling in cancer cell culture [60]. Thus, TNF implicates other inflammatory mediators in the tumorigenic signaling network and facilitates tissue remodeling.…”

“…In a gastric cell line, overexpression of constitutively active H286R CaMKII enhanced NF-κB- and AKT-mediated MMP-9 production, which supported cellular migration and invasion [103]. Infection with H. pylori can contribute to this effect by triggering calmodulin [60]. …”

In silico target fishing and pharmacological profiling for the isoquinoline alkaloids of Macleaya cordata (Bo Luo Hui)

“…The kinase calcium/calmodulin-dependent protein kinase II (CAMKII) was a regulator of intracellular Ca 2+ levels, which triggered activation of the transcription factor nuclear factor-kappa B (NF-κB) after T-cell receptor stimulation. An inhibitory effect of CAMKII on NF-κB was confirmed [61]. Phospholipase A2 (PLA2s) was a key enzyme in prostaglandin (PG) biosynthesis for discharging arachidonic acid.…”