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Alpha-kinase 1 functions upstream of IKKs to regulate NF-κB activation in Helicobacter infection

ABSTRACT: Gastric mucosa responds to the pathogen Helicobacter pylori (H. pylori) by producing and release of pro-inflammatory cytokines that activate the innate immune system mainly through activation of the transcription factor NF-κB. Although NF-κB signaling is well studied for many possible inducers, induction by H. pylori remains poorly understood. Here, we performed a high-throughput genome-wide RNAi screen for genes influencing H. pylori-induced NF-κB activation. In comparison to TNFα or IL‐1β NF‐κB signaling, we identified 21 proteins unique necessary for H. pylori NF-κB pathway and 24 factors that inhibited the activation. Furthermore, we present here the R/Bioconductor package Nested Effect Model for systematic use in high-throughput screens to classify newly identified factors. We identified alpha kinase 1 (ALPK1) as particular important for the H. pylori NF‐κB pathway without affecting TNFα or IL‐1β signaling. ALPK1 silencing inhibits activity of TAK1 and the IκB kinases (IKKs), degradation of the NF‐κB inhibitor IκBα, nuclear translocation of the NF‐κB subunit p65, and transcription of the NF‐κB target genes, e.g. IL‐8. Thus, we identify ALPK1 as a novel inflammatory regulator functioning particularly in the NF‐κB signaling network activated by H. pylori.

ORGANISM(S): Homo sapiens

PROVIDER: GSE89613 | GEO | 2019/09/02

REPOSITORIES: GEO

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Project description:Colitis is the common pathological lesion of inflammatory bowel diseases, the major chronic inflammatory diseases of intestinal tracts in humans. In this study, we investigated the therapeutic effects of ginger extract and its component zingerone in mice with 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis. Mice were administered with TNBS and/or various amounts of ginger and zingerone by an intrarectal route. The severity of colitis was evaluated by colonic weight/length ratio, macroscopic lesion, and histological examination. The mechanisms of ginger and zingerone were further elucidated by DNA microarray, ex vivo imaging, and immunohistochemical staining. Our data showed that treatment with ginger extract and zingerone ameliorated TNBS-induced colonic inflammation and injury in a dose-dependent manner. Pathway analysis of ginger- and zingerone-regulated gene expression profiles showed that ginger and zingerone significantly regulated cytokine-related pathways. Network analysis showed that nuclear factor-κB (NF-κB) and interleukin-1β (IL-1β) were key molecules involved in the expression of ginger- and zingerone-affected genes. Ex vivo imaging and immunohistochemical staining further verified that ginger and zingerone suppressed TNBS-induced NF-κB activation and decreased the NF-κB and IL-1β protein levels in the colon. In conclusion, our data showed that ginger improved the TNBS-induced colitis in mice via modulation of NF-κB activity and IL-1β signaling pathway. Moreover, zingerone might be the active component of ginger responsible for the amelioration of colitis induced by TNBS. A total of 24 mice was randomly divided into four groups of six mice: mock, mice were given with 0.1 ml of 50% ethanol; TNBS, mice were given with 250 mg/kg TNBS in 0.1 ml of 50% ethanol; TNBS/ginger, mice were administered with mixtures containing 250 mg/kg TNBS and various amounts of ginger extract in 0.1 ml of 50% ethanol; TNBS/zingerone, mice were given with mixtures containing 250 mg/kg TNBS and various amounts of zingerone in 0.1 ml of 50% ethanol. Mice were sacrificed seven days later for histochemical staining, RNA extraction, and ex vivo imaging.

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Alpha-kinase 1 functions upstream of IKKs to regulate NF-κB activation in Helicobacter infection

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