The inhibitory effects of roflumilast on lipopolysaccharide-induced nitric oxide production in RAW264.7 cells are mediated by heme oxygenase-1 and its product carbon monoxide

Kwak, Hyun Jung; Song, Jin Sook; No, Zaesung; Song, Jungsuk; Yang, Sung-Don; Cheon, Hyae Gyeong

doi:10.1007/s00011-005-1386-1

Cited by 34 publications

(20 citation statements)

References 29 publications

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“…In addition, these observations are in agreement with studies demonstrating that decreasing PDE4 activity with specific inhibitors causes a significant down-regulation in LPS-induced TNF expression and an inflammatory response in vitro and in vivo (Kwak et al, 2005;Ouagued et al, 2005;Hertz et al, 2009). Taken together, these observations strongly suggest that inhibition of LPSinduced up-regulation of PDE4B2 plays a major role in the ability of SAM to attenuate LPS-induced TNF production and related organ injury.…”

Section: Discussionsupporting

confidence: 90%

“…Of importance, in monocytes/ macrophages that predominantly express isoforms of PDE4 A, B, and D, it has been established that PDE4B is involved in LPS-induced signaling mediated by TLR-4 and is essential for LPS-induced TNF expression (Jin and Conti, 2002;Jin et al, 2005). Several studies including ours have shown that LPS-inducible TNF production by monocytes is markedly decreased when PDE activity is blocked by PDE4-specific inhibitors (Kwak et al, 2005;Ouagued et al, 2005;Gobejishvili et al, 2008). Peritoneal and lung macrophages, as well as peripheral leukocytes from Pde4b knockout mice, showed significantly attenuated production of TNF in response to LPS, whereas the responses of Pde4d(Ϫ/Ϫ) mice were similar to those of wild-type mice (Jin and Conti, 2002).…”

Section: Introductionmentioning

confidence: 72%

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S-Adenosylmethionine Decreases Lipopolysaccharide-Induced Phosphodiesterase 4B2 and Attenuates Tumor Necrosis Factor Expression via cAMP/Protein Kinase A Pathway

Gobejishvili

Avila²,

Barker³

et al. 2011

J Pharmacol Exp Ther

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S-Adenosylmethionine (SAM) treatment has anti-inflammatory, cytoprotective effects against endotoxin-induced organ injury. An important component of the anti-inflammatory action of SAM involves down-regulation of the lipopolysaccharide (LPS)-induced transcriptional induction of tumor necrosis factor-␣ (TNF) expression by monocytes/macrophages. We examined the effect of SAM on expression and activity of LPS-induced up-regulation of phosphodiesterase 4 (PDE4), which regulates cellular cAMP levels and TNF expression. LPS treatment of RAW 264.7, a mouse macrophage cell line, led to the induction of Pde4b2 mRNA expression with no effect on Pde4a or Pde4d. SAM pretreatment led to a significant decrease in LPS-induced up-regulation of Pde4b2 expression in both RAW 264.7 cells and primary human CD14 ϩ monocytes. Of note, the decreased Pde4b2 mRNA expression correlated with the SAM-dependent increase in the transcriptionally repressive histone H3 lysine 9 trimethylation on the Pde4b2 intronic promoter region. The SAM-mediated decrease in LPS-inducible Pde4b2 up-regulation resulted in an increase in cellular cAMP levels and activation of cAMP-dependent protein kinase A (PKA), which plays an inhibitory role in LPS-induced TNF production. In addition, SAM did not affect LPS-inducible inhibitor of nuclear factor-B degradation or nuclear factor-B (NF-B)-p65 translocation into the nucleus but rather inhibited NF-B transcriptional activity. These results demonstrate for the first time that inhibition of LPS-induced PDE4B2 up-regulation and increased cAMP-dependent PKA activation are significant mechanisms contributing to the anti-TNF effect of SAM. Moreover, these data also suggest that SAM may be used as an effective PDE4B inhibitor in the treatment of chronic inflammatory disorders in which TNF expression plays a significant pathogenic role.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 72%

S-Adenosylmethionine Decreases Lipopolysaccharide-Induced Phosphodiesterase 4B2 and Attenuates Tumor Necrosis Factor Expression via cAMP/Protein Kinase A Pathway

Gobejishvili

Avila²,

Barker³

et al. 2011

J Pharmacol Exp Ther

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“…Particularly, cAMP-specific PDE4, which is present in different tissues, is found to be the predominant PDE isoenzyme among 11 PDEs in human monocytes (4,18). Numerous studies have shown that LPS-inducible TNF production by monocytes is markedly decreased when PDE activity is blocked by PDE4-specific inhibitors (3,4,16,23,29,30,31,33,35). PDE4 isozyme has four isoforms, namely A, B, C, and D (18).…”

mentioning

confidence: 99%

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

Gobejishvili

Barve²,

Joshi‐Barve³

et al. 2008

American Journal of Physiology-Gastrointestinal and Liver Physi

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Enhanced PDE4B expression augments LPS-inducible TNF expression in ethanol-primed monocytes: relevance to alcoholic liver disease. Am J Physiol Gastrointest Liver Physiol 295: G718 -G724, 2008. First published August 7, 2008 doi:10.1152/ajpgi.90232.2008.-Increased plasma and hepatic TNF-␣ 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-B activation and TNF-␣ 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-␣ production by affecting NF-B 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-B activation and transcriptional activity and subsequent priming of monocytes/macrophages leading to enhanced LPS-inducible TNF-␣ production. Selective inhibition of PDE4 by rolipram abrogated LPS-mediated TNF-␣ expression at both protein and mRNA levels in control and ethanol-treated cells. Notably, PDE4 inhibition did not affect LPS-inducible NF-B activation but significantly decreased NF-B transcriptional activity. These findings strongly support the pathogenic role of PDE4B in the ethanolmediated priming of monocytes/macrophages and increased LPSinducible 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.DYSREGULATED TNF METABOLISM in alcoholic hepatitis (AH) was first described by us almost two decades ago with the observation that cultured monocytes from patients with AH spontaneously produced TNF and produced significantly more TNF in response to an LPS stimulus than control monocytes (20). Furthermore, we and others have shown that there are increased serum levels of TNF, increased monocyte TNF production, and hepatic immunohistochemical staining for TNF in AH that frequently correlate with disease severity and mortality (2,5,12,15,19,20,22,27). Although TNF plays an important role in the pathogenesis of liver injury and the clinical/biochemical abnormalities of AH (9, 20 -22), the mechanism(s) by which ethanol enhances TNF expression, particularly in monocytes/macrophages, is only beginning to be understood (6,14,37,38). We recently demonstrated that chronic ethanol exposure of monocytes/macropha...

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“…We previously reported that inducible NOS and HO-1/2 expression is involved in the secretion of IGF-I in MCF-7 cells [52]. Furthermore, expression of the cellular protection and oxidative stress resistance protein HO-1/2 is decreased in kidneys with RF [53] but recovers after EA [54]. However, our results show that rats with RF-induced hypertension respond to oxidative stress, which is reflected by TBARS, iNOS and HO-1/2 levels, and EA treatment inactivates these proteins.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Electroacupuncture on Insulin-Like Growth Factor-I and Oxidative Stress in an Animal Model of Renal Failure-Induced Hypertension

Yang

Choi

et al. 2012

Kidney Blood Press Res

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Background/Aims: The present study was performed to demonstrate the effect of electroacupuncture (EA) and acupuncture on renal failure (RF)-induced hypertension. Methods: We stimulated the Zusanli (ST36) and Taixi (KI3) acupoints in a rat model of RF-induced hypertension. Results: EA significantly reduced RF-induced hypertension (p < 0.05). In a histopathological study, increments in RF-induced glomerulosclerosis and tubulointerstitial fibrosis were attenuated by EA treatment (p < 0.05). The increase in albuminuria in the RF group was also reduced by EA treatment (p < 0.05). In blood analysis, the increment in RF-induced serum BUN and creatinine concentrations were decreased by EA (p < 0.05), and the decreases in RF-induced insulin-like growth factor-I (IGF-I) mRNA and protein levels were increased by EA in both the kidney and the serum (p < 0.05). The increases in RF-induced oxidative stress, e.g. inducible nitric oxide synthase, heme oxygenase and thiobarbituric acid-reactive substance expression, were significantly decreased in the RF-EA group (p < 0.01). Conclusion: These findings suggest that the anti-hypertensive mechanism of EA could be related to the effects of oxidative stress on IGF-I in RF-induced hypertension.

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The inhibitory effects of roflumilast on lipopolysaccharide-induced nitric oxide production in RAW264.7 cells are mediated by heme oxygenase-1 and its product carbon monoxide

Abstract: These results suggested that roflumilast exerts its anti-inflammatory effects in macrophages through a novel mechanism that involves the action of HO-1 and its product, CO.

Cited by 34 publications

References 29 publications

S-Adenosylmethionine Decreases Lipopolysaccharide-Induced Phosphodiesterase 4B2 and Attenuates Tumor Necrosis Factor Expression via cAMP/Protein Kinase A Pathway

S-Adenosylmethionine Decreases Lipopolysaccharide-Induced Phosphodiesterase 4B2 and Attenuates Tumor Necrosis Factor Expression via cAMP/Protein Kinase A Pathway

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

The Effect of Electroacupuncture on Insulin-Like Growth Factor-I and Oxidative Stress in an Animal Model of Renal Failure-Induced Hypertension

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