ArticleCell death & disease2021
TNF-α synergises with IFN-γ to induce caspase-8-JAK1/2-STAT1-dependent death of intestinal epithelial cells.
Article in Cell death & disease, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 117 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
117 citing papers in PubMed, 166 citations in OpenAlex.
- A yeast-derived postbiotic fermentate rapidly modulates inflammatory cytokines and immune surveillance markers in healthy adults: a randomized double-blind placebo-controlled cross-over trial.Frontiers in nutrition · 2026Trial
- Altered epithelial barrier functions in the colon of patients with spina bifida.Scientific reports · 2022Trial
- Unraveling the drug resistance web in IBD: The gut microbiota-immunity-epigenetics axis.Gut microbes · 2026Review
- Role of PANoptosis in the development of gastric immunity and related gastric mucosal disease (Review).Molecular medicine reports · 2026Review
- AMPK as a central regulator of necroptosis: mechanistic insights and therapeutic implications.Journal of physiology and biochemistry · 2026Review
- Loss of type I interferon signaling in Kupffer cells triggers viral spread and fatal liver damage in a mouse model of Crimean-Congo hemorrhagic fever.PLoS pathogens · 2026Article
- PANoptosis in the pathogenesis of myelodysplastic syndromes.Molecular oncology · 2026Review
- Persistent Gene Activation as a Molecular Signature of Ulcerative Colitis Progression to Colorectal Cancer.Digestive diseases and sciences · 2026Article
- In vitro modeling of inflammatory bowel diseases using a newly developed immunocompetent colon epithelial monolayer co-culture model.npj biomedical innovations · 2026Article
- Temporal transcriptomic profiling identifies core regulators in cytokine-induced gut barrier disruption in differentiated Caco-2 cells.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2026Article
- Pro-Inflammatory Cytokines as Core Mediators of Colonic Epithelial Barrier Dysfunction: Roles of TNF-α, IFN-γ, IL-1β, and IL-6.International journal of molecular sciences · 2026Review
- Porcine reproductive and respiratory syndrome virus N protein-mediated viral replication enhancement via interaction with host caspase-6.Journal of virology · 2026Article
- Tumor microenvironment-driven natural killer cell diversity: mechanisms and therapeutic opportunities.Cancer biology & medicine · 2026Review
- Oral Colon-Targeted Lipid Nanoparticles Enhance Upadacitinib Delivery and Efficacy in a Murine Model of Ulcerative Colitis.International journal of molecular sciences · 2026Article
- Differential effects of GVHD therapies on intestinal epithelium.Blood advances · 2026Article
- [Niranthin ameliorates Crohn's disease-like colitis in mice via antagonizing intestinal epithelial cell apoptosis and regulating intestinal Th1/Th2 immune homeostasis].Nan fang yi ke da xue xue bao = Journal of Southern Medical University · 2026Article
- Hydrogen sulfide rescues IFNγ/TNFα-induced intestinal epithelial barrier dysfunction by enhancing oxidative phosphorylation.Scientific reports · 2026Article
- CRISPR screens in the context of immune selection identify CHD1 and MAP3K7 as mediators of cancer immunotherapy resistance.Cell reports. Medicine · 2026Article
- Inflammatory bowel diseases: pathological mechanisms and therapeutic perspectives.Molecular biomedicine · 2026Review
- Proinflammatory cytokines modify CaFrontiers in physiology · 2026Article
57 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
19 authors at 5 institutions in 3 countries.
Funding
Abstract
Rewiring of host cytokine networks is a key feature of inflammatory bowel diseases (IBD) such as Crohn's disease (CD). Th1-type cytokines-IFN-γ and TNF-α-occupy critical nodes within these networks and both are associated with disruption of gut epithelial barrier function. This may be due to their ability to synergistically trigger the death of intestinal epithelial cells (IECs) via largely unknown mechanisms. In this study, through unbiased kinome RNAi and drug repurposing screens we identified JAK1/2 kinases as the principal and nonredundant drivers of the synergistic killing of human IECs by IFN-γ/TNF-α. Sensitivity to IFN-γ/TNF-α-mediated synergistic IEC death was retained in primary patient-derived intestinal organoids. Dependence on JAK1/2 was confirmed using genetic loss-of-function studies and JAK inhibitors (JAKinibs). Despite the presence of biochemical features consistent with canonical TNFR1-mediated apoptosis and necroptosis, IFN-γ/TNF-α-induced IEC death was independent of RIPK1/3, ZBP1, MLKL or caspase activity. Instead, it involved sustained activation of JAK1/2-STAT1 signalling, which required a nonenzymatic scaffold function of caspase-8 (CASP8). Further modelling in gut mucosal biopsies revealed an intercorrelated induction of the lethal CASP8-JAK1/2-STAT1 module during ex vivo stimulation of T cells. Functional studies in CD-derived organoids using inhibitors of apoptosis, necroptosis and JAKinibs confirmed the causative role of JAK1/2-STAT1 in cytokine-induced death of primary IECs. Collectively, we demonstrate that TNF-α synergises with IFN-γ to kill IECs via the CASP8-JAK1/2-STAT1 module independently of canonical TNFR1 and cell death signalling. This non-canonical cell death pathway may underpin immunopathology driven by IFN-γ/TNF-α in diverse autoinflammatory diseases such as IBD, and its inhibition may contribute to the therapeutic efficacy of anti-TNFs and JAKinibs.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.