The role of tumour necrosis factor-  and tumour necrosis factor receptor signalling in inflammation-associated systemic genotoxicity

SummaryTumour necrosis factor-α (TNF-α) is upregulated in many inflammatory diseases and is also a potent agent for microparticle (MP) generation. Here, we describe an essential role of TNF-α in the production of endothelial cell-derived microparticles (EMPs) in vivo and the function of TNF-α-induced EMPs in endothelial cells. We found that TNF-α rapidly increased blood levels of EMPs in mice. Treatment of human umbilical vein endothelial cells (HUVECs) with TNF-α also induced EMP formation in a time-dependent manner. Silencing of TNF receptor (TNFR)-1 or inhibition of the nuclear factor-κB (NF-κB) in HUVECs impaired the production of TNF-α-induced EMP. Incubation of HUVECs with PKH-67-stained EMPs showed that endothelial cells readily engulfed EMPs, and the engulfed TNF-α-induced EMPs promoted the expression of pro-apoptotic molecules and upregulated intercellular adhesion molecule-1 level on the cell surface, which led to monocyte adhesion. Collectively, our findings indicate that the generation of TNF-α-induced EMPs was mediated by TNFR1 or NF-κB and that EMPs can contribute to apoptosis and inflammation of endothelial cells.

Download Full-text

The dual role of p55 tumour necrosis factor-? receptor in Actinobacillus actinomycetemcomitans-induced experimental periodontitis: host protection and tissue destruction

Clinical & Experimental Immunology ◽

10.1111/j.1365-2249.2006.03260.x ◽

2006 ◽

Vol 0 (0) ◽

pp. 061127015327001-??? ◽

Cited By ~ 11

Author(s):

G. P. Garlet ◽

C. R. B. Cardoso ◽

A. P. Campanelli ◽

B. R. Ferreira ◽

M. J. Avila-Campos ◽

...

Keyword(s):

Tumour Necrosis Factor ◽

Tumour Necrosis ◽

Dual Role ◽

Actinobacillus Actinomycetemcomitans ◽

Tumour Necrosis Factor Receptor ◽

Tissue Destruction ◽

Host Protection ◽

Experimental Periodontitis ◽

Necrosis Factor

Download Full-text

Induction of stress-activated protein kinases/c-Jun N-terminal kinases by the p55 tumour necrosis factor receptor does not require sphingomyelinases

Biochemical Journal ◽

10.1042/bj3330343 ◽

1998 ◽

Vol 333 (2) ◽

pp. 343-350 ◽

Cited By ~ 13

Author(s):

Dieter ADAM ◽

Andrea RUFF ◽

Astrid STRELOW ◽

Katja WIEGMANN ◽

Martin KRÖNKE

Keyword(s):

Protein Kinases ◽

Tumour Necrosis Factor ◽

Tumour Necrosis ◽

Proteolytic Degradation ◽

Tumour Necrosis Factor Receptor ◽

General Role ◽

Jnk Activation ◽

Uv C ◽

Necrosis Factor

Ceramide has been implicated in the activation of stress-activated protein kinases/c-Jun N-terminal kinases (SAPK/JNK). Binding of tumour necrosis factor (TNF) to its 55 kDa receptor (TR55) leads to the generation of ceramide through activation of either acid or neutral sphingomyelinase (A/N-SMase) as well as to potent activation of SAPK/JNK. We have examined a putative role of both N- and A-SMase in the TR55-dependent activation of SAPK/JNK. The analysis of TR55 deletion mutants expressed in 70Z/3 pre-B cells revealed that activation of SAPK/JNK occurs independently of N-SMase. Although both SAPK/JNK and A-SMase are activated by the death domain of TR55, pharmacological prevention of the TR55-dependent activation of A-SMase, or proteolytic degradation of A-SMase in 70Z/3 cells, did not impair SAPK/JNK activation, indicating that SAPK/JNK are not secondary to A-SMase. In addition, proteolytic degradation of A-SMase also did not affect SAPK/JNK activation by ultraviolet (UV-C) irradiation, arguing against a general role of A-SMase in stress-mediated responses. Furthermore, fibroblasts from Niemann–Pick A patients deficient in A-SMase did not show altered activation of SAPK/JNK in response to either TNF or UV-C. These results suggest that TR55 can activate SAPK/JNK without direct participation of sphingomyelinases or ceramide.

Download Full-text