Modulation of the Activation of Extracellular Signal-Regulated Kinase (ERK) and the Production of Inflammatory Mediators by ADP-Ribosylation Inhibitors

2003 ◽  
Vol 384 (10-11) ◽  
pp. 1509-1513 ◽  
Author(s):  
C. Le Page ◽  
J. Wietzerbin
Keyword(s):  
Inflammatory Mediators ◽  
Nuclear Factor Κb ◽  
Oxygen Species ◽  
Extracellular Signal Regulated Kinase ◽  
Adp Ribosylation ◽  
Raw264.7 Macrophages ◽  
Extracellular Signal ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

Abstract ADP-ribosylation is involved in nuclear factor κB (NF-κB)-dependent gene expression induced by lipopolysaccharide in murine macrophages. Here we have investigated the mechanism by which ADP-ribosylation inhibitors block signaling pathways induced in macrophages. In RAW264.7 macrophages the inducers of NF-κB activate the production of reactive oxygen species and three mitogenactivated protein kinases (MAPK), the extracellular signal regulated kinase (ERK), the c-jun N-terminal kinase/stress-activated protein kinase (JNK), and p38. We demonstrate that ADP-ribosylation inhibitors specifically inhibit ERK MAPK activation and reduce the release of inflammatory mediators such as tumor necrosis factor α (TNF-α), IL-6 and nitrite.

Lipopolysaccharide stimulation of ERK1/2 increases TNF-α production via Egr-1

2002 ◽  
Vol 282 (6) ◽  
pp. C1205-C1211 ◽  
Author(s):  
Liang Shi ◽  
Raj Kishore ◽  
Megan R. McMullen ◽  
Laura E. Nagy
Keyword(s):  
Dominant Negative ◽  
Protein Accumulation ◽  
Extracellular Signal Regulated Kinase ◽  
Early Growth Response ◽  
Extracellular Signal ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor ◽  
Dependent Mechanism

Lipopolysaccharide (LPS) is a potent activator of tumor necrosis factor-α (TNF-α) production by macrophages. LPS stimulates the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and increases TNF-α mRNA and protein accumulation in RAW 264.7 murine macrophages. However, the role of ERK1/2 activation in mediating LPS-stimulated TNF-α production is not well understood. Inhibition of ERK1/2 activation with PD-98059 or overexpression of dominant negative ERK1/2 decreased LPS-induced TNF-α mRNA quantity. LPS rapidly increased early growth response factor (Egr)-1 binding to the TNF-α promoter; this response was blunted in cells treated with PD-98059 or transfected with dominant-negative ERK1/2. Using a chloramphenicol acetyltransferase reporter gene linked to the Egr-1 promoter, we show that LPS increased Egr-1 promoter activity via an ERK1/2-dependent mechanism. These results delineate the role of ERK1/2 activation of Egr-1 activity in mediating LPS-induced increases in TNF-α mRNA expression in macrophages.

EPEC-activated ERK1/2 participate in inflammatory response but not tight junction barrier disruption

2001 ◽  
Vol 281 (4) ◽  
pp. G890-G898 ◽  
Author(s):  
Suzana D. Savkovic ◽  
Akila Ramaswamy ◽  
Athanasia Koutsouris ◽  
Gail Hecht
Keyword(s):  
Tight Junction ◽  
Signaling Cascades ◽  
Extracellular Signal Regulated Kinase ◽  
Intestinal Epithelia ◽  
Extracellular Signal ◽  
Tnf Α ◽  
Functional Consequences ◽  
First Time ◽  
Necrosis Factor ◽  
Iκbα Degradation

Enteropathogenic Escherichia coli (EPEC) alters many functions of the host intestinal epithelia. Inflammation is initiated by activation of nuclear factor (NF)-κB, and paracellular permeability is enhanced via a Ca2+- and myosin light-chain kinase (MLCK)-dependent pathway. The aims of this study were to identify signaling pathways by which EPEC triggers inflammation and to determine whether these pathways parallel or diverge from those that alter permeability. EPEC-induced phosphorylation and degradation of the primary inhibitor of NF-κB (IκBα) were tumor necrosis factor (TNF)-α and interleukin (IL)-1β independent. In contrast to Salmonella typhimurium, EPEC-stimulated IκBα degradation and IL-8 expression did not require Ca2+. Instead, extracellular signal-regulated kinase (ERK)-1/2 was significantly and rapidly activated. ERK1/2 inhibitors attenuated IκBα degradation and IL-8 expression. Although ERK1/2 can activate MLCK, its inhibition had no impact on EPEC disruption of the tight junction barrier. In conclusion, EPEC-induced inflammation 1) is TNF-α and IL-1β receptor independent, 2) utilizes pathways differently from S. typhimurium, 3) requires ERK1/2, and 4) employs signals that are distinct from those that alter permeability. This is the first time that EPEC-activated signaling cascades have been linked to independent functional consequences.

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