scholarly journals c-Jun NH2-Terminal Kinase Is Essential for the Regulation of AP-1 by Tumor Necrosis Factor

2003 ◽  
Vol 23 (8) ◽  
pp. 2871-2882 ◽  
Author(s):  
Juan-Jose Ventura ◽  
Norman J. Kennedy ◽  
Jennifer A. Lamb ◽  
Richard A. Flavell ◽  
Roger J. Davis
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Signal Transduction Pathway ◽  
Binding Activity ◽  
Dna Binding Activity ◽  
Related Transcription Factor ◽  
Regulated Gene Expression ◽  
Necrosis Factor

ABSTRACT The c-Jun NH2-terminal kinase (JNK) is activated by the cytokine tumor necrosis factor (TNF). This pathway is implicated in the regulation of AP-1-dependent gene expression by TNF. To examine the role of the JNK signaling pathway, we compared the effects of TNF on wild-type and Jnk1 −/− Jnk2 −/− murine embryo fibroblasts. We show that JNK is required for the normal regulation of AP-1 by TNF. The JNK-deficient cells exhibited decreased expression of c-Jun, JunD, c-Fos, Fra1, and Fra2; decreased phosphorylation of c-Jun and JunD; and decreased AP-1 DNA binding activity. The JNK-deficient cells also exhibited defects in the regulation of the AP-1-related transcription factor ATF2. These changes were associated with marked defects in TNF-regulated gene expression. The JNK signal transduction pathway is therefore essential for AP-1 transcription factor regulation in cells exposed to TNF.

scholarly journals NF-κB1 (p50) Is Upregulated in Lipopolysaccharide Tolerance and Can Block Tumor Necrosis Factor Gene Expression

1999 ◽  
Vol 67 (4) ◽  
pp. 1553-1559 ◽  
Author(s):  
Stefan Kastenbauer ◽  
H. W. Löms Ziegler-Heitbrock
Keyword(s):  
Gene Expression ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Binding Activity ◽  
Transactivation Domain ◽  
Monocytic Cell ◽  
Monocytic Cell Line ◽  
Hek 293 ◽  
Tnf Gene ◽  
Necrosis Factor

ABSTRACT Monocytes respond to lipopolysaccharide (LPS) stimulation with a rapid expression of the tumor necrosis factor (TNF) gene. Upon repeated LPS stimulation there is, however, little production of TNF mRNA and protein; i.e., the cells are tolerant to LPS. Analysis of NF-κB proteins in gel shift assays demonstrated that the DNA binding activity that is induced by LPS stimulation in tolerant cells consists mainly of p50-p50 homodimers. Since p50 can bind to DNA but lacks a transactivation domain, this may explain the blockade of TNF gene expression. We now show that in the monocytic cell line Mono Mac 6, this inability to respond can be largely ascribed to NF-κB, since a reporter construct directed by a trimeric NF-κB motif is strongly transactivated by LPS stimulation of naive cells whereas LPS-tolerant cells exhibit only low activity. Also, Western blot analyses of proteins extracted from purified nuclei showed mobilization of threefold-higher levels of p50 protein in tolerant compared to naive cells, while mobilization of p65 was unaltered. Overexpression of p50 in HEK 293 cells resulted in a strong reduction of p65-driven TNF promoter activity at the levels of both luciferase mRNA and protein. These data support the concept that an upregulation of p50 is instrumental in LPS tolerance in human monocytes.

Interleukin-9 Regulates NF-κB Activity Through BCL3 Gene Induction

Blood ◽  
1999 ◽  
Vol 93 (12) ◽  
pp. 4318-4327 ◽  
Author(s):  
Mélisande Richard ◽  
Jamila Louahed ◽  
Jean-Baptiste Demoulin ◽  
Jean-Christophe Renauld
Keyword(s):  
Gene Expression ◽  
Tumor Necrosis ◽  
Transcriptional Activity ◽  
Binding Activity ◽  
Transient Transfection ◽  
Regulatory Pathway ◽  
Dna Binding Activity ◽  
Interleukin 9 ◽  
Necrosis Factor ◽  
Stat Pathway

Abstract BCL3 encodes a protein with close homology to IκB proteins and interacts with p50 NF-κB homodimers. However, the regulation and transcriptional activity of BCL3 remain ill-defined. We observed here that interleukin-9 (IL-9) and IL-4, but not IL-2 or IL-3, transcriptionally upregulated BCL3 expression in T cells and mast cells. BCL3 induction by IL-9 was detected as soon as 4 hours after stimulation and appeared to be dependent on the Jak/STAT pathway. IL-9 stimulation was associated with an increase in p50 homodimers DNA binding activity, which was mimicked by stableBCL3 expression. This contrasts with tumor necrosis factor (TNF)-dependent NF-κB activation, which occurs earlier, involves p65/p50 dimers, and is dependent on IκB degradation. Moreover, IL-9 stimulation or BCL3 transient transfection similarly inhibited NF-κB–mediated transcription in response to TNF. Taken together, our observations show a new regulatory pathway for the NF-κB transcription factors through STAT-dependent upregulation ofBCL3 gene expression.

Interleukin-9 Regulates NF-κB Activity Through BCL3 Gene Induction

Blood ◽  
1999 ◽  
Vol 93 (12) ◽  
pp. 4318-4327
Author(s):  
Mélisande Richard ◽  
Jamila Louahed ◽  
Jean-Baptiste Demoulin ◽  
Jean-Christophe Renauld
Keyword(s):  
Gene Expression ◽  
Tumor Necrosis ◽  
Transcriptional Activity ◽  
Binding Activity ◽  
Transient Transfection ◽  
Regulatory Pathway ◽  
Dna Binding Activity ◽  
Interleukin 9 ◽  
Necrosis Factor ◽  
Stat Pathway

BCL3 encodes a protein with close homology to IκB proteins and interacts with p50 NF-κB homodimers. However, the regulation and transcriptional activity of BCL3 remain ill-defined. We observed here that interleukin-9 (IL-9) and IL-4, but not IL-2 or IL-3, transcriptionally upregulated BCL3 expression in T cells and mast cells. BCL3 induction by IL-9 was detected as soon as 4 hours after stimulation and appeared to be dependent on the Jak/STAT pathway. IL-9 stimulation was associated with an increase in p50 homodimers DNA binding activity, which was mimicked by stableBCL3 expression. This contrasts with tumor necrosis factor (TNF)-dependent NF-κB activation, which occurs earlier, involves p65/p50 dimers, and is dependent on IκB degradation. Moreover, IL-9 stimulation or BCL3 transient transfection similarly inhibited NF-κB–mediated transcription in response to TNF. Taken together, our observations show a new regulatory pathway for the NF-κB transcription factors through STAT-dependent upregulation ofBCL3 gene expression.

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