scholarly journals TNF-α synergises with IFN-γ to induce caspase-8-JAK1/2-STAT1-dependent death of intestinal epithelial cells

2021 ◽  
Vol 12 (10) ◽  
Author(s):  
Jerzy A. Woznicki ◽  
Nisha Saini ◽  
Peter Flood ◽  
Subhasree Rajaram ◽  
Ciaran M. Lee ◽  
...  
Keyword(s):  
Cell Death ◽  
Epithelial Cells ◽  
Intestinal Epithelial Cells ◽  
Ex Vivo ◽  
Caspase 8 ◽  
Causative Role ◽  
Intestinal Epithelial ◽  
Cell Death Pathway ◽  
Tnf Α ◽  
Ifn Γ

AbstractRewiring 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.

Proinflammatory cytokines TNF-α and IFN-γ alter laminin expression under an apoptosis-independent mechanism in human intestinal epithelial cells

2004 ◽  
Vol 287 (3) ◽  
pp. G592-G598 ◽  
Author(s):  
Caroline Francoeur ◽  
Fabrice Escaffit ◽  
Pierre H. Vachon ◽  
Jean-François Beaulieu
Keyword(s):  
Growth Factor ◽  
Epithelial Cells ◽  
Proinflammatory Cytokines ◽  
Intestinal Epithelial Cells ◽  
Intestinal Epithelial ◽  
Laminin 5 ◽  
Cell Functions ◽  
Tnf Α ◽  
Independent Mechanism ◽  
Ifn Γ

Laminins are basement membrane molecules that mediate cell functions such as adhesion, proliferation, migration, and differentiation. In the normal small intestine, laminin-5 and -10 are mainly expressed at the base of villus cells. However, in Crohn's disease (CD), a major redistribution of these laminins to the crypt region of the inflamed ileal mucosa has been observed, suggesting a possible relationship between laminin expression and cytokine and/or growth factor production, which is also altered in CD. The aim of this study was to test the hypothesis that proinflammatory cytokines can modulate laminin expression by intestinal epithelial cells. The effect of TNF-α, IFN-γ, IL-1β, IL-6, and transforming growth factor (TGF)-β was analyzed on the expression of laminins in the normal human intestinal epithelial crypt (HIEC) cell line. When treated with a single cytokine, HIEC cells secreted small amounts of laminin-5 and -10. Only TNF-α and TGF-β induced a slight increase in the secretion of these laminins. However, in combination, TNF-α and IFN-γ synergistically stimulated the secretion of both laminin-5 and -10 in HIEC cells. Transcript analyses suggested that the upregulation of the two laminins might depend on distinct mechanisms. Interestingly, the TNF-α and IFN-γ combination was also found to significantly promote apoptosis. However, the effect of cytokines on the secretion of laminins was maintained even after completely blocking apoptosis by inhibiting caspase activities. These results demonstrate that laminin production is specifically modulated by the proinflammatory cytokines TNF-α and IFN-γ in intestinal epithelial cells under an apoptosis-independent mechanism.

TNF-α and IFN-γ regulate the expression of the NOD2 (CARD15) gene in human intestinal epithelial cells

2003 ◽  
Vol 124 (4) ◽  
pp. 1001-1009 ◽  
Author(s):  
Philip Rosenstiel ◽  
Massimo Fantini ◽  
Karen Bräutigam ◽  
Tanja Kühbacher ◽  
Georg H. Waetzig ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Intestinal Epithelial Cells ◽  
Intestinal Epithelial ◽  
Human Intestinal Epithelial Cells ◽  
Tnf Α ◽  
Ifn Γ ◽  
Card15 Gene

TNF-α and IFN-γ regulate the expression of the NOD2 (CARD15) gene in human intestinal epithelial cells

2003 ◽  
Vol 124 (4) ◽  
pp. A111 ◽  
Author(s):  
Philip Rosenstiel ◽  
Massimo Fantini ◽  
Karen Braeutigam ◽  
Georg Waetzig ◽  
Tanja Kuehbacher ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Intestinal Epithelial Cells ◽  
Intestinal Epithelial ◽  
Human Intestinal Epithelial Cells ◽  
Tnf Α ◽  
Ifn Γ ◽  
Card15 Gene

scholarly journals Stress granule formation mediates the inhibition of colonic Hsp70 translation by interferon-γ and tumor necrosis factor-α

2010 ◽  
Vol 298 (4) ◽  
pp. G481-G492 ◽  
Author(s):  
Shien Hu ◽  
Erika C. Claud ◽  
Mark W. Musch ◽  
Eugene B. Chang
Keyword(s):  
Epithelial Cells ◽  
Intestinal Epithelial Cells ◽  
Interferon Γ ◽  
Stress Granule ◽  
Intestinal Epithelial ◽  
Granule Formation ◽  
Tnf Α ◽  
Ifn Γ ◽  
Factor Α ◽  
Necrosis Factor

Mucosal inflammation, through cytokines such as interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α), has many effects on the intestinal epithelium, including selective translational inhibition of the cytoprotective protein heat shock protein 70 (Hsp70). To further elucidate the mechanisms underlying this effect, we examined the role of stress granules in mediating the actions of these proinflammatory cytokines. Using conditionally immortalized young adult mouse colonic epithelial cells, we demonstrate that IFN-γ and TNF-α, which upregulate eukaryotic initiation factor-α (eIF-2α) phosphorylation and reduce Hsp70 translation, significantly enhance stress granule formation in heat-shocked intestinal epithelial cells. The IFN-γ and TNF-α effects in upregulation of stress granule formation and downregulation of Hsp70 were eIF-2α dependent, and the effect could be negated by blocking eIF-2α phosphorylation with use of an RNA-dependent protein kinase inhibitor. Correspondingly, IFN-γ and TNF-α increased binding of cytoplasmic proteins to the 3′-untranslated region of Hsp70 mRNA, suggesting specific recruitment of Hsp70 to stress granules as the mechanism of IFN-γ and TNF-α inhibition of Hsp70 translation. We thus report a novel linkage between inflammatory cytokine production, stress granule formation, and Hsp70 translation inhibition, providing additional insights into the response of intestinal epithelial cells to inflammatory stress.

Modulation of complement C3, C4, and factor B production in human intestinal epithelial cells: differential effects of TNF-α, IFN-γ, and IL-4

1995 ◽  
Vol 2 (4) ◽  
pp. 251-259 ◽  
Author(s):  
Akira Andoh ◽  
Yoshihide Fujiyama ◽  
Kenichi Sumiyoshi ◽  
Keiko Hodohara ◽  
Okabe Hidetoshi ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Intestinal Epithelial Cells ◽  
Complement C3 ◽  
Intestinal Epithelial ◽  
Factor B ◽  
Differential Effects ◽  
Human Intestinal Epithelial Cells ◽  
Tnf Α ◽  
Ifn Γ

NF-κB activation and susceptibility to apoptosis after polyamine depletion in intestinal epithelial cells

2001 ◽  
Vol 280 (5) ◽  
pp. G992-G1004 ◽  
Author(s):  
Li Li ◽  
Jaladanki N. Rao ◽  
Barbara L. Bass ◽  
Jian-Ying Wang
Keyword(s):  
Cell Death ◽  
Epithelial Cells ◽  
Nuclear Translocation ◽  
Intestinal Epithelial Cells ◽  
Apoptotic Cell ◽  
Binding Activity ◽  
Cell Renewal ◽  
Intestinal Epithelial ◽  
Tnf Α ◽  
Induced Apoptosis

The maintenance of intestinal mucosal integrity depends on a balance between cell renewal and cell death, including apoptosis. The natural polyamines, putrescine, spermidine, and spermine, are essential for mucosal growth, and decreasing polyamine levels cause G1 phase growth arrest in intestinal epithelial (IEC-6) cells. The present study was done to determine changes in susceptibility of IEC-6 cells to apoptosis after depletion of cellular polyamines and to further elucidate the role of nuclear factor-κB (NF-κB) in this process. Although depletion of polyamines by α-difluoromethylornithine (DFMO) did not directly induce apoptosis, the susceptibility of polyamine-deficient cells to staurosporine (STS)-induced apoptosis increased significantly as measured by changes in morphological features and internucleosomal DNA fragmentation. In contrast, polyamine depletion by DFMO promoted resistance to apoptotic cell death induced by the combination of tumor necrosis factor-α (TNF-α) and cycloheximide. Depletion of cellular polyamines also increased the basal level of NF-κB proteins, induced NF-κB nuclear translocation, and activated the sequence-specific DNA binding activity. Inhibition of NF-κB binding activity by sulfasalazine or MG-132 not only prevented the increased susceptibility to STS-induced apoptosis but also blocked the resistance to cell death induced by TNF-α in combination with cycloheximide in polyamine-deficient cells. These results indicate that 1) polyamine depletion sensitizes intestinal epithelial cells to STS-induced apoptosis but promotes the resistance to TNF-α-induced cell death, 2) polyamine depletion induces NF-κB activation, and 3) disruption of NF-κB function is associated with altered susceptibility to apoptosis induced by STS or TNF-α. These findings suggest that increased NF-κB activity after polyamine depletion has a proapoptotic or antiapoptotic effect on intestinal epithelial cells determined by the nature of the death stimulus.

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