Nonsteroidal anti-inflammatory drug metabolism potentiates interferon alfa signaling by increasing STAT1 phosphorylation

Giambartolomei, Stefania; Artini, Marco; Almerighi, Cristiana; Moavero, Sabrina Maria; Levrero, Massimo; Balsano, Clara

doi:10.1002/hep.510300224

Cited by 37 publications

(26 citation statements)

References 25 publications

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“…[34][35][36][37] Some reports have indicated the failure of NSAIDs and interferon combination therapy in improving interferon-resistant chronic hepatitis C, 34,38 whereas other authors, using ketoprofen plus interferon, have reported an improved virological response in chronic hepatitis C patients. 35 Giambartolomei et al 39,40 reported that indomethacin potentiates the interferon-␣ signaling pathway by increasing signal transducer and activator of transcription 1 phosphorylation in vitro, improving cellular response. It must be noted that the aforementioned studies used NSAIDs with different biochemical activities and did not include comparable groups of HCV patients.…”

Section: Discussionmentioning

confidence: 99%

Acetylsalicylic acid inhibits hepatitis C virus RNA and protein expression through cyclooxygenase 2 signaling pathways

et al. 2008

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It has been reported that salicylates (sodium salicylate and aspirin) inhibit the replication of flaviviruses, such as Japanese encephalitis virus and dengue virus. Therefore, we considered it important to test whether acetylsalicylic acid (ASA) had anti-hepatitis C virus (HCV) activity. To this end, we examined the effects of ASA on viral replication and protein expression, using an HCV subgenomic replicon cell culture system. We incubated Huh7 replicon cells with 2-8 mM ASA for different times and measured HCV-RNA and protein levels by northern blot, real-time polymerase chain reaction, and western analysis, respectively. We found that ASA had a suppressive effect on HCV-RNA and protein levels (nearly 58%). ASA-dependent inhibition of HCV expression was not mediated by the 5 -internal ribosome entry site or 3 -untranslated regions, as determined by transfection assays using bicistronic constructs containing these regulatory regions. However, we found that HCVinduced cyclooxygenase 2 (COX-2) messenger RNA and protein levels and activity and these effects were down-regulated by ASA, possibly by a nuclear factor kappa B-independent mechanism. We also observed that the ASA-dependent inhibition of viral replication was due in part to inhibition of COX-2 and activation of p38 and mitogen-activated protein kinase/ extracellular signal-regulated kinase kinase 1/2 (MEK1/2) mitogen-activated protein kinases (MAPKs). Inhibition of these kinases by SB203580 and U0126, respectively, and by short interfering RNA silencing of p38 and MEK1 MAPK prevented the antiviral effect of ASA. Taken together, our findings suggest that the anti-HCV effect of ASA in the Huh7 replicon cells is due to its inhibitory effect on COX-2 expression, which is mediated in part by the activation of MEK1/2/p38 MAPK. Conclusion: These findings suggest the possibility that ASA could be an excellent adjuvant in the treatment of chronic HCV infection. (HEPATOLOGY 2008;47:1462-1472

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Section: Discussionmentioning

confidence: 99%

Acetylsalicylic acid inhibits hepatitis C virus RNA and protein expression through cyclooxygenase 2 signaling pathways

et al. 2008

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“…[62][63][64][65] Although suppression of Th1 responses by means of NF-B inhibition occurs at ASA doses well above the therapeutic range, [25][26][27] lower concentrations of ASA can enhance (by means of inhibition of monocyte PG generation) the in vitro and ex vivo expression of at least some Th1 cytokines and inherently counteract Th2 responses. 21,22,24 Therefore, NSAIDs have been evaluated as possible adjuvants of Th1-driven antiviral responses 17,66 and in the management of Th2-associated and IL-4-associated conditions such as atopic asthma or rhinitis. 67,68 It was shown that topical treatment with lysin-ASA or SA, but not IM, can prevent the early asthmatic response to inhaled allergen, 69 a finding consistent with the critical role of IL-4 in the development of such reactions.…”

Section: Discussionmentioning

confidence: 99%

“…8,10 On the other hand, salicylates were reported to activate mitogen-activated protein kinases and enhance interferon (IFN) signaling. 13,16,17 These overall effects of salicylates are compounded by their ability to induce the release of potent anti-inflammatory mediators, such as adenosine and 15-epi-lipoxin A 4 . 9,14 Taken together, these observations support the idea that the multiple therapeutic effects of ASA derive from its ability to regulate a network of biochemical and cellular events more complex than was initially thought.…”

Section: Introductionmentioning

confidence: 99%

Selective inhibition of interleukin-4 gene expression in human T cells by aspirin

Cianferoni¹,

Schroeder²,

Kim³

et al. 2001

Blood

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IntroductionAspirin (acetylsalicylic acid [ASA]) is the oldest and most widely used nonsteroidal anti-inflammatory drug (NSAID). Although several other classes of NSAIDs have become available since the introduction of ASA in 1899, this agent and structurally related salicylates still provide the mainstay of therapy for inflammatory musculoskeletal disorders. In addition, these compounds have been shown to be effective in the management and prevention of an increasingly diverse array of noninflammatory conditions, including coronary and cerebral ischemia and gastrointestinal cancer. 1,2 Both the therapeutic properties of NSAIDs and their side effects have been ascribed to their ability to inhibit generation of prostaglandin (PG) and thromboxane by interfering with the intracellular enzyme cyclo-oxygenase (COX). 3 It is widely accepted that the anti-inflammatory actions of NSAIDs are mediated by inhibition of the inducible COX isoform COX-2, whereas their detrimental effects on gastric mucosa viability and platelet function are due mostly to inhibition of COX-1. 4 The relative effectiveness of several NSAIDs against the 2 isozymes varies considerably. 5 In particular, although ASA is a relatively effective, irreversible inhibitor of COX-1, its effects on COX-2 activity are negligible. 5 This probably explains why higher doses of ASA are required in the treatment of chronic inflammatory diseases than are sufficient to inhibit PG generation in different experimental models in vitro. 6 However, the in vivo anti-inflammatory and anticancer activity of nonacetylated salicylates, which are poor overall inhibitors of both COX-1 and COX-2, is almost superimposable to that of ASA or even more potent NSAIDs, such as diclofenac. 7 Indeed, given the short serum half-life of ASA (15 minutes), the serum concentrations of salicylic acid (SA), its major nonacetylated metabolite, are better predictors of therapeutic effectiveness than the concentrations of ASA itself. 6 In the light of these observations, it has been speculated that inhibition of PG production cannot fully account for the therapeutic potential of ASA and related salicylates. 6 Indeed, several studies showed that these compounds have a spectrum of biochemical and pharmacologic effects that are not related to COX inhibition and not shared with other NSAIDs. [8][9][10][11][12][13][14][15] A major finding was the discovery that ASA and SA can interfere with the activation of critical transcription factors, such as nuclear factor (NF) B (NF-B) and activator protein 1 (AP-1). 8,10 On the other hand, salicylates were reported to activate mitogen-activated protein kinases and enhance interferon (IFN) signaling. 13,16,17 These overall effects of salicylates are compounded by their ability to induce the release of potent anti-inflammatory mediators, such as adenosine and 15-epi-lipoxin A 4 . 9,14 Taken together, these observations support the idea that the multiple therapeutic effects of ASA derive from its ability to regulate a network of biochemical and cellular events mo...

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“…Interestingly, NSAID and NS398 treatment of Chang liver and HepG2 cells results in increased response to IFN-α, suggesting that COX-2 expression may result in IFN therapy resistance (32). In this context, the induction of COX-2 by HBx would help the virus to evade the immune system, favoring chronic HBV infection and the progression to cirrhosis and HCC.…”

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confidence: 99%

The hepatitis B virus X protein promotes tumor cell invasion by inducing membrane-type matrix metalloproteinase-1 and cyclooxygenase-2 expression

Lara‐Pezzi¹,

Gómez-Gaviro²,

Gálvez³

et al. 2002

J. Clin. Invest.

152

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Hepatocellular carcinoma is strongly associated with chronic infection by the hepatitis B virus (HBV) and has poor prognosis due to intrahepatic metastasis. HBx is often the only HBV protein detected in hepatic tumor cells; however, its contribution to tumor invasion and metastasis has not been established so far. In this work, we show that HBx enhances tumor cell invasion, both in vivo and in vitro. The increased invasive capacity induced by HBx is mediated by an upregulation of membrane-type 1 matrix metalloproteinase (MT1-MMP) expression, which in turn activates matrix metalloproteinase-2. Induction of both MT1-MMP expression and cell invasion by HBx is dependent on cyclooxygenase-2 (COX-2) activity. In addition, HBx upregulates the expression of COX-2, which is mediated by the transcriptional activation of the COX-2 gene promoter in a nuclear factor of activated T cell–dependent (NF-AT–dependent) manner. These results demonstrate the ability of HBx to promote tumor cell invasion by a mechanism involving the upregulation of MT1-MMP and COX-2 and provide new insights into the mechanism of action of this viral protein and its involvement in tumor metastasis and recurrence of hepatocellular carcinoma

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Nonsteroidal anti-inflammatory drug metabolism potentiates interferon alfa signaling by increasing STAT1 phosphorylation

Cited by 37 publications

References 25 publications

Acetylsalicylic acid inhibits hepatitis C virus RNA and protein expression through cyclooxygenase 2 signaling pathways

Acetylsalicylic acid inhibits hepatitis C virus RNA and protein expression through cyclooxygenase 2 signaling pathways

Selective inhibition of interleukin-4 gene expression in human T cells by aspirin

The hepatitis B virus X protein promotes tumor cell invasion by inducing membrane-type matrix metalloproteinase-1 and cyclooxygenase-2 expression

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