Sensitization by interleukin-6 of rat hepatocytes to tumor necrosis factor α-induced apoptosis

Böer, Ulrike; Fennekohl, Alexandra; Püschel, Gerhard

doi:10.1016/s0168-8278(03)00090-4

Cited by 11 publications

(5 citation statements)

References 26 publications

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“…Interleukin (IL)-6-dependent upregulation of TNFR1 mRNA has previously been shown to be involved in rat hepatocyte sensitization to TNFa-induced apoptosis. 25 Conversely, in our cell models, including NIH3T3 and pancreatic cancer BxPC-3 cells, sst2 did not affect TNFR1 mRNA expression but rather upregulated TNFR1 protein, 10 suggesting that sst2 acts at a post-transcriptional level.…”

Section: Discussionmentioning

confidence: 62%

Novel synergistic mechanism for sst2 somatostatin and TNFα receptors to induce apoptosis: crosstalk between NF-κB and JNK pathways

et al. 2006

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Somatostatin is a multifunctional hormone that modulates cell proliferation, differentiation and apoptosis. Mechanisms for somatostatin-induced apoptosis are at present mostly unsolved. Therefore, we investigated whether somatostatin receptor subtype 2 (sst2) induces apoptosis in the nontransformed murine fibroblastic NIH3T3 cells. Somatostatin receptor subtype 2 expression induced an executioner caspase-mediated apoptosis through a tyrosine phosphatase SHP-1 (Src homology domain phosphatase-1)-dependent stimulation of nuclear factor kappa B (NF-jB) activity and subsequent inhibition of the mitogenactivated protein kinase JNK. Tumor necrosis factor a (TNFa) stimulated both NF-jB and c-Jun NH2-terminal kinase (JNK) activities, which had opposite action on cell survival. Importantly, sst2 sensitized NIH3T3 cells to TNFa-induced apoptosis by (1) upregulating TNFa receptor protein expression, and sensitizing to TNFa-induced caspase-8 activation; (2) enhancing TNFamediated activation of NF-jB, resulting in JNK inhibition and subsequent executioner caspase activation and cell death. We have here unraveled a novel signaling mechanism for a G protein-coupled receptor, which directly triggers apoptosis and crosstalks with a death receptor to enhance death ligand-induced apoptosis. Somatostatin is a regulatory peptide which is mostly expressed in the central and peripheral nervous system, in the gastro-intestinal tract and in the pancreas. Somatostatin acts via a family of five G protein-coupled receptors (GPCR), somatostatin receptor subtypes 1-5 (sst1-sst5) that are variably expressed throughout numerous tissues ranging from the central nervous system to the endocrine and immune systems. 1 Somatostatin or its analogues promote growth inhibition of various normal and tumor cells, both in vitro and in vivo. Somatostatin affects cell growth indirectly by inhibiting either trophic or growth factor synthesis and/or secretion, or their respective intracellular pathways. Somatostatin antiproliferative action also results from a direct blockade of cell cycle and/or induction of apoptosis. 2 Whereas somatostatin effect on cell cycle arrest has been extensively studied, mechanisms for somatostatin-induced apoptosis and receptor subtype implication are only partially elucidated. Somatostatin has been shown to induce cell death in both normal and tumoral cell models 3-9 . Among the five somatostatin receptors, sst3 and sst2 have been found to play a critical role in somatostatin-induced apoptosis of normal and tumor cells, respectively. 3,5,10 Mechanisms for somatostatin apoptotic action were shown to rely on the mitochondrial pathway through activation either of sst2 or sst3. However, signaling pathways coupling sst2 receptor to apoptosis have been partially elucidated.We have previously demonstrated that expression of sst2 in the nontransformated murine fibroblastic NIH3T3 cells results in a cell growth inhibition, which was dependent on the activation of the tyrosine phosphatase Src homology domain phosphatase-1 (SHP-1). 11 sst2...

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Section: Discussionmentioning

confidence: 62%

Novel synergistic mechanism for sst2 somatostatin and TNFα receptors to induce apoptosis: crosstalk between NF-κB and JNK pathways

et al. 2006

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“…Furthermore, increased sensitivity to LPS in some mutant mice has been related to high circulating levels of IL-6 (74). IL-6 can also enhance TNF␣-induced apoptosis of hepatocytes sensitized by actinomycin D (75). However, IL-6-deficient mice appeared equally sensitive to TNF␣ even after sensitization with D-galactosamine (76).…”

Section: Discussionmentioning

confidence: 99%

Role of FAN in Tumor Necrosis Factor-α and Lipopolysaccharide-induced Interleukin-6 Secretion and Lethality in d-Galactosamine-sensitized Mice

Malagarie‐Cazenave

Ségui

Lévêque

et al. 2004

Journal of Biological Chemistry

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Tumor necrosis factor (TNF) ␣-induced neutral sphingomyelinase-mediated generation of ceramide, a bioactive lipid molecule, is transduced by the adaptor protein FAN, which binds to the intracellular region of the CD120a TNF␣ receptor. FAN-deficient mice do not exhibit any gross abnormality. To further explore the functions of FAN in vivo and because CD120a-deficient mice are resistant to endotoxin-induced liver failure and lethality, we investigated the susceptibility of FANdeficient animals to lipopolysaccharide (LPS). We show that after D-galactosamine sensitization, FAN-deficient mice were partially resistant to LPS-and TNF␣-induced lethality. Although LPS challenge resulted in a hepatic ceramide content lower in mutant mice than in control animals, it triggered similar histological alterations, caspase activation, and DNA fragmentation in the liver. Interestingly, LPS-induced elevation of IL-6 (but not TNF␣) serum concentrations was attenuated in FANdeficient mice. A less pronounced secretion of IL-6 was also observed after LPS or TNF␣ treatment of cultured peritoneal macrophages and embryonic fibroblasts isolated from FAN-deficient mice, as well as in human fibroblasts expressing a mutated FAN. Finally, we show that D-galactosamine-sensitized IL-6-deficient mice were partially resistant to endotoxin-induced liver apoptosis and lethality. These findings highlight the role of FAN and IL-6 in the inflammatory response initiated by endotoxin, implicating TNF␣.

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“…Because IL-6 can promote TNFα-mediated apoptosis in vitro (44), another potential explanation for the protective effects of IL-6 deletion is that pulmonary parenchymal cell death is attenuated when MV-induced IL-6 production is reduced. Inhibition of either pulmonary epithelial or endothelial cell apoptosis might result in a more intact permeability barrier.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-6 mediates pulmonary vascular permeability in a two-hit model of ventilator-associated lung injury

Gürkan

Zielinski

et al. 2011

Experimental Lung Research

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To test the hypothesis that IL-6 contributes to the development of ventilator-associated lung injury (VALI), IL-6-deficient (IL6−/−) and wild-type control (WT) mice received intratracheal hydrochloric acid followed by randomization to MV (MV+IT HCl) or spontaneous ventilation (IT HCl). After 4 hr, injury was assessed by estimation of lung lavage protein concentration and total and differential cell counts, wet/dry lung weight ratio, pulmonary cell death, histologic inflammation score (LIS), and parenchymal myeloperoxidase (MPO) concentration. Vascular endothelial growth factor (VEGF) concentration was measured in lung lavage and homogenate, as IL-6 and stretch both regulate expression of this potent mediator of permeability. MV-induced increases in alveolar barrier dysfunction and lavage VEGF were attenuated in IL6−/− mice as compared with WT controls, whereas tissue VEGF concentration increased. The effects of IL-6 deletion on alveolar permeability and VEGF concentration were inflammation-independent, as parenchymal MPO concentration, LIS, and lavage total and differential cell counts did not differ between WT and IL6−/− mice following IT HCl+MV. These data support a role for IL-6 in promoting VALI in this two-hit model. Strategies to interfere with IL-6 expression or signaling may represent important therapeutic targets to limit the injurious effects of MV in inflamed lungs.

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Sensitization by interleukin-6 of rat hepatocytes to tumor necrosis factor α-induced apoptosis

Cited by 11 publications

References 26 publications

Novel synergistic mechanism for sst2 somatostatin and TNFα receptors to induce apoptosis: crosstalk between NF-κB and JNK pathways

Novel synergistic mechanism for sst2 somatostatin and TNFα receptors to induce apoptosis: crosstalk between NF-κB and JNK pathways

Role of FAN in Tumor Necrosis Factor-α and Lipopolysaccharide-induced Interleukin-6 Secretion and Lethality in d-Galactosamine-sensitized Mice

Interleukin-6 mediates pulmonary vascular permeability in a two-hit model of ventilator-associated lung injury

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