Caspases, S-adenosyl methionine and anti-tumor necrosis factor alpha signaling for protection in ethanol induced apoptosis in normal human hepatocytes

Tumor necrosis factor alpha (TNF-alpha) and interleukin-1 (IL-1) activate transcription of the TSG-6 gene in normal human fibroblasts through a promoter region (-165 to -58) that encompasses an AP-1 and a NF-IL6 site. We show by deletion analysis and substitution mutagenesis that both sites are necessary for activation by TNF-alpha. Activation by IL-1 requires the NF-IL6 site and is enhanced by the AP-1 site. These results suggest that the NF-IL6 and AP-1 family transcription factors functionally cooperate to mediate TNF-alpha and IL-1 signals. Consistent with this possibility, IL-1 and TNF-alpha markedly increase the binding of Fos and Jun to the AP-1 site, and NF-IL6 activates the native TSG-6 promoter. Activation by NF-IL6 requires an intact NF-IL6 site and is modulated by the ratio of activator to inhibitor NF-IL6 isoforms that are translated from different in-frame AUGs. However, the inhibitor isoform can also bind to the AP-1 site and repress AP-1 site-mediated transcription. The finding that the inhibitor isoform antagonizes activation of the native TSG-6 promoter by IL-1 and TNF-alpha suggests that NF-IL6 has a physiologic role in these cytokine responses. Thus, the functionally distinct NF-IL6 isoforms cooperate with Fos and Jun to positively and negatively regulate the native TSG-6 promoter by TNF-alpha and IL-1.

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Critical involvement of transmembrane tumor necrosis factor-alpha in endothelial programmed cell death mediated by ionizing radiation and bacterial endotoxin

Blood ◽

10.1182/blood.v86.11.4184.bloodjournal86114184 ◽

1995 ◽

Vol 86 (11) ◽

pp. 4184-4193 ◽

Cited By ~ 129

Author(s):

G Eissner ◽

F Kohlhuber ◽

M Grell ◽

M Ueffing ◽

P Scheurich ◽

...

Keyword(s):

Cell Death ◽

Tumor Necrosis Factor ◽

Programmed Cell Death ◽

Ionizing Radiation ◽

Tumor Necrosis Factor Alpha ◽

Tumor Necrosis ◽

Necrosis Factor Alpha ◽

Factor Alpha ◽

Induced Apoptosis ◽

Necrosis Factor

In this report, we show that ionizing radiation (IR) at a clinically relevant dose (4 Gy) causes apoptosis in macrovascular and microvascular human endothelial cells. Treatment of irradiated cells with a low dose of bacterial endotoxin (LPS), similar to the levels observed in serum during endotoxemia, enhanced the rate of apoptosis, although LPS alone was unable to induce programmed cell death. The cytokine and endotoxin antagonist interleukin-10 (IL-10) reduced the rate of LPS + IR-induced apoptosis to levels obtained with irradiation alone. Using neutralizing antibodies against tumor necrosis factor- alpha (TNF), we could show crucial involvement of TNF in the LPS- mediated enhancement of IR-induced apoptosis, but not in the IR-induced apoptosis per se. However, further analysis strongly suggested the transmembrane form of TNF (mTNF), but not soluble TNF, to be accountable for the LPS-mediated cytotoxic effects. Studies with anatagonistic receptor specific antibodies clearly showed that TNF receptor type I (TR60) is essential and sufficient to elicit this effect. These findings are of potential clinical importance because they may disclose a relevant mechanism that leads to endothelial damage after radiotherapy or total body irradiation used for conditioning in bone marrow transplantation and that may thus contribute to transplant related complications, especially in association with endotoxemia or related inflammatory states.

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Tumor Necrosis Factor Alpha-Induced Apoptosis Requires p73 and c-ABL Activation Downstream of RB Degradation

Molecular and Cellular Biology ◽

10.1128/mcb.24.10.4438-4447.2004 ◽

2004 ◽

Vol 24 (10) ◽

pp. 4438-4447 ◽

Cited By ~ 45

Author(s):

B. Nelson Chau ◽

Tung-Ti Chen ◽

Yisong Y. Wan ◽

James DeGregori ◽

Jean Y. J. Wang

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis Factor Alpha ◽

Tumor Necrosis ◽

Wild Type ◽

Necrosis Factor Alpha ◽

Abl Tyrosine Kinase ◽

Tnf Α ◽

Factor Alpha ◽

Induced Apoptosis ◽

Necrosis Factor

ABSTRACT The retinoblastoma protein (RB) suppresses cell proliferation and apoptosis. We have previously shown that RB degradation is required for tumor necrosis factor alpha (TNF-α) to induce apoptosis. We show here the identification of two apoptotic effectors, i.e., c-ABL tyrosine kinase and p73, which are activated by TNF-α following RB degradation. In cells expressing a degradation-resistant RB protein (RB-MI), TNF-α does not activate c-ABL. RB-MI also inhibits TNF-α-mediated activation of p73. Genetic deletion and pharmacological inhibition of c-ABL or p73 diminish the apoptotic response to TNF-α in human cell lines and mouse fibroblasts. Thymocytes isolated from RbMI/MI , Abl −/−, or p73 −/− mice are resistant to TNF-α-induced apoptosis compared to their wild-type counterparts. This is in contrast to p53 −/− thymocytes, which exhibit a wild-type level of apoptosis in response to TNF-α. Thus, c-ABL and p73 contribute to apoptosis induced by TNF-α, in addition to their role in promoting DNA damage-associated cell death.

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