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Human interleukin 23 receptor induces cell apoptosis in mammalian cells by intrinsic mitochondrial pathway associated with the down-regulation of RAS/mitogen-activated protein kinase and signal transducers and activators of transcription factor 3 signaling pathways.

ABSTRACT: The composition of IL-23R complex is similar to that of the IL-12 receptor (IL-12R) complex with a shared IL-12R-?1 chain. The IL-12R-?1 heterodimerizes with IL-23R and IL-12R-?2 to form IL-23R and IL-12R complexes, respectively. The IL-12R-?2 has been shown to function as a tumor suppressor gene and apoptotic inducer. However, whether IL-23R also functions in cell apoptosis is currently unknown. In this study, we demonstrate for the first time that overexpression of IL-23R markedly induces cell apoptosis in both 293ET and HeLa cells. The activations of caspase 3 and caspase 9 are induced by IL-23R. Mechanistic study reveals that IL-23R markedly inhibits RAS/MAPK and STAT3 but not STAT1 and PI-3K/Akt signaling pathways in both 293ET and HeLa cells. Overexpression of IL-23R significantly up-regulates IL-12R?1 expression but not IL-23? and IL-12? expressions in both cell lines. Therefore, our data strongly indicates that IL-23R is able to induce cell apoptosis by activating the intrinsic mitochondrial pathways associated with the inhibition in RAS/MAPK and STAT3 activations in mammalian cells.

SUBMITTER: Shi WY

PROVIDER: S-EPMC3876134 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Human interleukin 23 receptor induces cell apoptosis in mammalian cells by intrinsic mitochondrial pathway associated with the down-regulation of RAS/mitogen-activated protein kinase and signal transducers and activators of transcription factor 3 signaling pathways.

Shi Wei-Ye WY Che Chang-Yan CY Liu Li L

International journal of molecular sciences 20131218 12

The composition of IL-23R complex is similar to that of the IL-12 receptor (IL-12R) complex with a shared IL-12R-β1 chain. The IL-12R-β1 heterodimerizes with IL-23R and IL-12R-β2 to form IL-23R and IL-12R complexes, respectively. The IL-12R-β2 has been shown to function as a tumor suppressor gene and apoptotic inducer. However, whether IL-23R also functions in cell apoptosis is currently unknown. In this study, we demonstrate for the first time that overexpression of IL-23R markedly induces cell ...[more]

PMID: 24351840

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Project description:ObjectivePsoriasis and multiple sclerosis (MS) are complex immune diseases that are mediated by T cells and share multiple comorbidities. Previous studies have suggested psoriatic patients are at higher risk of MS; however, causal relationships between the two conditions remain unclear. Through epidemiology and genetics, we provide a comprehensive understanding of the relationship, and share molecular factors between psoriasis and MS.MethodsWe used logistic regression, trans-disease meta-analysis and Mendelian randomization. Medical claims data were included from 30 million patients, including 141,544 with MS and 742,919 with psoriasis. We used genome-wide association study summary statistics from 11,024 psoriatic, 14,802 MS cases, and 43,039 controls for trans-disease meta-analysis, with additional summary statistics from 5 million individuals for Mendelian randomization.ResultsPsoriatic patients have a significantly higher risk of MS (4,637 patients with both diseases; odds ratio [OR] 1.07, p = 1.2 × 10-5 ) after controlling for potential confounders. Using inverse variance and equally weighted trans-disease meta-analysis, we revealed >20 shared and opposing (direction of effect) genetic loci outside the major histocompatibility complex that showed significant genetic colocalization (in COLOC and COLOC-SuSiE v5.1.0). Co-expression analysis of genes from these loci further identified distinct clusters that were enriched among pathways for interleukin-17/tumor necrosis factor-α (OR >39, p < 1.6 × 10-3 ) and Janus kinase-signal transducers and activators of transcription (OR 35, p = 1.1 × 10-5 ), including genes, such as TNFAIP3, TYK2, and TNFRSF1A. Mendelian randomization found psoriasis as an exposure has a significant causal effect on MS (OR 1.04, p = 5.8 × 10-3 ), independent of type 1 diabetes (OR 1.05, p = 4.3 × 10-7 ), type 2 diabetes (OR 1.08, p = 2.3 × 10-3 ), inflammatory bowel disease (OR 1.11, p = 1.6 × 10-11 ), and vitamin D level (OR 0.75, p = 9.4 × 10-3 ).InterpretationBy investigating the shared genetics of psoriasis and MS, along with their modifiable risk factors, our findings will advance innovations in treatment for patients suffering from comorbidities. ANN NEUROL 2023;94:384-397.

Dataset Information

Human interleukin 23 receptor induces cell apoptosis in mammalian cells by intrinsic mitochondrial pathway associated with the down-regulation of RAS/mitogen-activated protein kinase and signal transducers and activators of transcription factor 3 signaling pathways.

Publications

Human interleukin 23 receptor induces cell apoptosis in mammalian cells by intrinsic mitochondrial pathway associated with the down-regulation of RAS/mitogen-activated protein kinase and signal transducers and activators of transcription factor 3 signaling pathways.

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