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 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.

scholarly journals Black Carrot (Daucus carota ssp. sativus var. Atrorubens Alef.) Extract Protects against Ethanol-induced Liver Injury via the Suppression of Phosphodiesterase 4 mRNA Expression

2021 ◽  
Vol 9 (2) ◽  
Author(s):  
Kitano A ◽  
◽  
Norikura T ◽  
Matsui-Yuasa I ◽  
Shimakawa H ◽  
...  
Keyword(s):  
Liver Disease ◽  
Alcoholic Liver Disease ◽  
Control Level ◽  
Intracellular Camp ◽  
Transcriptional Level ◽  
Protective Effects ◽  
Black Carrot ◽  
Camp Levels

We examined the protective effects of Black Carrot Extract (BCE) on Alcoholic Liver Disease (ALD) using in vivo and in vitro models. In an in vivo ethanol-Carbon Tetrachloride (CCl4)-treated rat model, BCE treatment suppressed serum alanine aminotransferase and aspartate aminotransferase activity. BCE also suppressed ethanol- and CCl4-induced alcoholic liver disease. Furthermore, we observed that the BCE or butanol-extracted fraction of BCE (BCE-BuOH) recovered the cell viability of in vitro ethanol-treated hepatocytes. BCE-BuOH also suppressed the production of reactive oxygen species induced by ethanol to the control level. Moreover, BCE-BuOH regulated the activities of three alcoholic metabolism-related enzymes: cytochrome P450 2E1 activity was suppressed at the posttranslational level, alcohol dehydrogenase activity was increased at the posttranslational level, and aldehyde dehydrogenase 2 activity was increased at the transcriptional level. Novel findings in this study include an increase in intracellular Cyclic Adenosine 3’,5’-Monophosphate (cAMP) levels in hepatocytes with the simultaneous addition of ethanol and BCE-BuOH and the suppression of changes in the activities of three enzymes upon treatment with an inhibitor of cAMP-dependent protein kinase. Our study also found that BCE-BuOH suppressed the expression of phosphodiesterase 4b mRNA, which increased intracellular cAMP levels. These results suggest that BCE is useful for the treatment of ALD.

scholarly journals Polymodal Sensory Thalamic Inputs to the Rat Lateral Amygdala are Facilitated by Chronic Ethanol Exposure and Regulate Withdrawal-associated Anxiety

2019 ◽  
Author(s):  
Melissa Morales ◽  
Molly M. McGinnis ◽  
Ann M. Chappell ◽  
Brian C. Parrish ◽  
Brian A. McCool
Keyword(s):  
Glutamate Release ◽  
Ethanol Exposure ◽  
Synaptic Function ◽  
Chronic Ethanol ◽  
Thalamic Nuclei ◽  
Lateral Amygdala ◽  
Systemic Injection ◽  
Chronic Ethanol Exposure ◽  
Thalamic Projections

AbstractThalamic projections to the lateral amygdala regulate the acquisition of conditioned aversive and reward-related behaviors. Recent work suggests that exposure to chronic ethanol up-regulates presynaptic function of lateral amygdala stria terminalis inputs which contain projections from somatosensory thalamic nuclei. To understand potential contributions by thalamic inputs and their role in the expression of withdrawal-associated aversive behaviors, we integrated optogenetic and chemogenetic approaches with in vitro measures of synaptic function and anxiety-like behavior. We found that expression of Channelrhodopsin in the caudal extension of the posterior thalamic group (cPO) produced monosynaptic glutamatergic synaptic responses in lateral amygdala principal neurons that could be inhibited by co-expression of the hM4-Gi-DREADD. Chronic ethanol exposure increased glutamate release from these cPO terminals but did not impact inhibition by the DREADD agonist, CNO. Systemic injection of CNO specifically reduced withdrawal-related increases in anxiety-like behaviors in animals expressing the Gi-DREADD in cPO. And, microinjection of CNO directly into the lateral amygdala mimicked this anti-anxiety effect. These findings suggest that the cPO-LA circuit is vulnerable to chronic ethanol exposure and plays an important role in regulating anxiety-like behavior following chronic ethanol exposure.

scholarly journals Dysregulation of hepatic zinc transporters in a mouse model of alcoholic liver disease

2014 ◽  
Vol 307 (3) ◽  
pp. G313-G322 ◽  
Author(s):  
Qian Sun ◽  
Qiong Li ◽  
Wei Zhong ◽  
Jiayang Zhang ◽  
Xiuhua Sun ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Peroxide ◽  
Liver Disease ◽  
Ethanol Exposure ◽  
Zinc Transporters ◽  
Protein Abundance ◽  
Time Points ◽  
Chronic Ethanol Exposure ◽  
Zinc Levels

Zinc deficiency is a consistent phenomenon observed in patients with alcoholic liver disease, but the mechanisms have not been well defined. The objective of this study was to determine if alcohol alters hepatic zinc transporters in association with reduction of hepatic zinc levels and if oxidative stress mediates the alterations of zinc transporters. C57BL/6 mice were pair-fed with the Lieber-DeCarli control or ethanol diets for 2, 4, or 8 wk. Chronic alcohol exposure reduced hepatic zinc levels, but increased plasma and urine zinc levels, at all time points. Hepatic zinc finger proteins, peroxisome proliferator-activated receptor-α (PPAR-α) and hepatocyte nuclear factor 4α (HNF-4α), were downregulated in ethanol-fed mice. Four hepatic zinc transporter proteins showed significant alterations in ethanol-fed mice compared with the controls. ZIP5 and ZIP14 proteins were downregulated, while ZIP7 and ZnT7 proteins were upregulated, by ethanol exposure at all time points. Immunohistochemical staining demonstrated that chronic ethanol exposure upregulated cytochrome P-450 2E1 and caused 4-hydroxynonenal accumulation in the liver. For the in vitro study, murine FL-83B hepatocytes were treated with 5 μM 4-hydroxynonenal or 100 μM hydrogen peroxide for 72 h. The results from in vitro studies demonstrated that 4-hydroxynonenal treatment altered ZIP5 and ZIP7 protein abundance, and hydrogen peroxide treatment changed ZIP7, ZIP14, and ZnT7 protein abundance. These results suggest that chronic ethanol exposure alters hepatic zinc transporters via oxidative stress, which might account for ethanol-induced hepatic zinc deficiency.

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