scholarly journals Enhanced PDE4B expression augments LPS-inducible TNF expression in ethanol-primed monocytes: relevance to alcoholic liver disease

2008 ◽  
Vol 295 (4) ◽  
pp. G718-G724 ◽  
Author(s):  
Leila Gobejishvili ◽  
Shirish Barve ◽  
Swati Joshi-Barve ◽  
Craig McClain
Keyword(s):  
Liver Disease ◽  
Alcoholic Liver Disease ◽  
Alcoholic Hepatitis ◽  
Transcriptional Activity ◽  
Subsequent Development ◽  
Ethanol Exposure ◽  
Chronic Ethanol ◽  
Mrna Levels ◽  
Chronic Ethanol Exposure ◽  
Tnf Α

Increased plasma and hepatic TNF-α expression is well documented in patients with alcoholic hepatitis and is implicated in the pathogenesis of alcoholic liver disease. We have previously shown that monocytes from patients with alcoholic hepatitis show increased constitutive and LPS-induced NF-κB activation and TNF-α production. Our recent studies showed that chronic ethanol exposure significantly decreased cellular cAMP levels in both LPS-stimulated and unstimulated monocytes and Kupffer cells, leading to an increase in LPS-inducible TNF-α production by affecting NF-κB activation and induction of TNF mRNA expression. Accordingly, the mechanisms underlying this ethanol-induced decrease in cellular cAMP leading to an increase in TNF expression were examined in monocytes/macrophages. In this study, chronic ethanol exposure was observed to significantly increase LPS-inducible expression of cAMP-specific phosphodiesterase (PDE)4B that degrades cellular cAMP. Increased PDE4B expression was associated with enhanced NF-κB activation and transcriptional activity and subsequent priming of monocytes/macrophages leading to enhanced LPS-inducible TNF-α production. Selective inhibition of PDE4 by rolipram abrogated LPS-mediated TNF-α expression at both protein and mRNA levels in control and ethanol-treated cells. Notably, PDE4 inhibition did not affect LPS-inducible NF-κB activation but significantly decreased NF-κB transcriptional activity. These findings strongly support the pathogenic role of PDE4B in the ethanol-mediated priming of monocytes/macrophages and increased LPS-inducible TNF production and the subsequent development of alcoholic liver disease (ALD). Since enhanced TNF expression plays a significant role in the evolution of clinical and experimental ALD, its downregulation via selective PDE4B inhibitors could constitute a novel therapeutic approach in the treatment of ALD.

Chronic ethanol-mediated decrease in cAMP primes macrophages to enhanced LPS-inducible NF-κB activity and TNF expression: relevance to alcoholic liver disease

2006 ◽  
Vol 291 (4) ◽  
pp. G681-G688 ◽  
Author(s):  
Leila Gobejishvili ◽  
Shirish Barve ◽  
Swati Joshi-Barve ◽  
Silvia Uriarte ◽  
Zhenyuan Song ◽  
...  
Keyword(s):  
Liver Disease ◽  
Alcoholic Liver Disease ◽  
Ethanol Exposure ◽  
Chronic Ethanol ◽  
Production Studies ◽  
Chronic Ethanol Exposure ◽  
Tnf Α ◽  
Tnf Gene ◽  
Camp Levels

Increased plasma and hepatic TNF-α activity has been implicated in the pathogenesis of alcoholic liver disease (ALD). We previously reported that monocytes from alcoholic patients show enhanced constitutive as well as LPS-inducible NF-κB activation and TNF-α production. Studies in monocytes have shown that cAMP plays an important role in regulating TNF-α expression, and elevation of cellular cAMP suppresses TNF-α production. The effects of chronic ethanol exposure on the cellular levels of cAMP as well as TNF expression in monocytes were examined in vitro and in rat primary hepatic Kupffer cells obtained from a clinically relevant enteral alcohol feeding model of ALD. Chronic ethanol exposure significantly decreased cellular cAMP levels in both LPS-stimulated and unstimulated monocytes. Consistent with the decrease in cAMP levels, ethanol led to an increase in LPS-inducible TNF-α production by affecting NF-κB activation and induction of TNF mRNA expression, without any change in TNF mRNA stability. Enhancement of cellular cAMP with dibutyryl cAMP abrogated LPS-mediated TNF-α expression in ethanol-treated cells. Importantly, cAMP did not affect LPS-inducible NF-κB activation but significantly decreased its transcriptional activity. Together, these data strongly suggest that ethanol can synergize with LPS to upregulate the induction of TNF gene expression and consequent TNF overproduction by decreasing the cellular cAMP levels in monocytes/macrophages. Furthermore, these data also support the notion that cAMP-elevating agents could constitute an effective therapeutic approach in attenuating or preventing the progression of liver disease in alcoholic patients.

scholarly journals Disrupted Thalamic T-Type Ca2+ Channel Expression and Function During Ethanol Exposure and Withdrawal

2011 ◽  
Vol 105 (2) ◽  
pp. 528-540 ◽  
Author(s):  
J. D. Graef ◽  
T. W. Huitt ◽  
B. K. Nordskog ◽  
J. H. Hammarback ◽  
D. W. Godwin
Keyword(s):  
Chronic Alcoholism ◽  
Ethanol Exposure ◽  
Chronic Ethanol ◽  
Network Activity ◽  
Mrna Levels ◽  
Chronic Ethanol Exposure ◽  
Daily Variations ◽  
Channel Expression ◽  
Low Threshold ◽  
And Function

Chronic ethanol exposure produces profound disruptions in both brain rhythms and diurnal behaviors. The thalamus has been identified as a neural pacemaker of both normal and abnormal rhythms with low-threshold, transient (T-type) Ca2+ channels participating in this activity. We therefore examined T-type channel gene expression and physiology in the thalamus of C57Bl/6 mice during a 4-wk schedule of chronic intermittent ethanol exposures in a vapor chamber. We found that chronic ethanol disrupts the normal daily variations of both thalamic T-type channel mRNA levels and alters thalamic T-type channel gating properties. The changes measured in channel expression and function were associated with an increase in low-threshold bursts of action potentials during acute withdrawal periods. Additionally, the observed molecular and physiological alterations in the channel properties in wild-type mice occurred in parallel with a progressive disruption in the normal daily variations in theta (4–9 Hz) power recorded in the cortical electroencephalogram. Theta rhythms remained disrupted during a subsequent week of withdrawal but were restored with the T-type channel blocker ethosuximide. Our results demonstrate that a key ion channel underlying the generation of thalamic rhythms is altered during chronic ethanol exposure and withdrawal and may be a novel target in the management of abnormal network activity due to chronic alcoholism.

Destabilization of TNF-α mRNA by retinoic acid in hepatic macrophages: implications for alcoholic liver disease

2001 ◽  
Vol 281 (3) ◽  
pp. E420-E429 ◽  
Author(s):  
Kenta Motomura ◽  
Mitsuru Ohata ◽  
Michael Satre ◽  
Hidekazu Tsukamoto
Keyword(s):  
Retinoic Acid ◽  
Liver Disease ◽  
Alcoholic Liver Disease ◽  
Mrna Stability ◽  
Transforming Growth Factor ◽  
Cytokine Expression ◽  
Retinol Binding Protein ◽  
Mrna Levels ◽  
Tnf Α ◽  
Specific Ligand

Retinoic acid (RA) inhibits hepatic macrophage (HM) cytokine expression, and retinoids are depleted in alcoholic liver disease (ALD). However, neither the causal link between the two nor the mechanism underlying RA-mediated HM inhibition is known. The aim of the present study was to determine the mechanism of RA-induced inhibition of HM tumor necrosis factor (TNF)-α expression and the relevance of this regulation to ALD. Treatment with all- trans RA (500 nM) caused a 50% inhibition in lipopolysaccharide (LPS)-stimulated TNF-α expression by cultured normal rat HM. The mRNA levels for inducible nitric oxide synthase, interleukin (IL)-6, IL-1α, and IL-1β were also reduced, whereas those for transforming growth factor-β1, MMP-9, and membrane cofactor protein-1 were unaffected. The inhibitory effect on TNF-α expression was reproduced by LG268, a retinoid X receptor (RXR)-specific ligand, but not by TTNPB, an RA receptor (RAR)-specific ligand. RA did not alter LPS-stimulated NF-kB and activation protein-1 binding but significantly decreased TNF-α mRNA stability in HM. HM isolated from the ALD model showed significant decreases in all- trans RA (−48%) and 9- cis RA (−61%) contents, RA response element (RARE) binding, and mRNA levels for RARβ, RXRα, and cytosolic retinol binding protein-1, whereas TNF-α mRNA expression was induced. TNF-α mRNA stability was increased in these cells, and an ex vivo treatment with all- trans RA normalized both RARβ and TNF-α mRNA levels. These results demonstrate the RA-induced destabilization of TNF-α mRNA by cultured HM and the association of RA depletion with increased TNF-α mRNA stability in HM from experimental ALD. These findings suggest that RA depletion primes HM for proinflammatory cytokine expression in ALD, at least in part, via posttranscriptional regulation.

Chronic ethanol exposure differentially regulates NOS1 mRNA levels depending on rat brain area

2003 ◽  
Vol 338 (3) ◽  
pp. 221-224 ◽  
Author(s):  
Mickaël Naassila ◽  
Olivier Pierrefiche ◽  
Françoise J. Beaugé ◽  
Nadia Sébire ◽  
Martine Daoust
Keyword(s):  
Rat Brain ◽  
Brain Area ◽  
Ethanol Exposure ◽  
Chronic Ethanol ◽  
Mrna Levels ◽  
Chronic Ethanol Exposure

Chronic ethanol exposure induces alterations in the nucleocytoplasmic transport in growing astrocytes

2008 ◽  
Vol 106 (4) ◽  
pp. 1914-1928 ◽  
Author(s):  
María Pilar Marín ◽  
Mónica Tomas ◽  
Guillermo Esteban-Pretel ◽  
Luis Megías ◽  
Carmen López-Iglesias ◽  
...  
Keyword(s):  
Nucleocytoplasmic Transport ◽  
Ethanol Exposure ◽  
Chronic Ethanol ◽  
Chronic Ethanol Exposure
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