Differential effects of acyclic nucleoside phosphonates on nitric oxide and cytokines in rat hepatocytes and macrophages

Kostecká, Petra; Holý, Antonı́n; Farghali, Hassan; Zı́dek, Zdeňek; Kmoníčková, Eva

doi:10.1016/j.intimp.2011.12.005

Cited by 10 publications

(11 citation statements)

References 32 publications

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“…The absence of an effect on IL-6 secretion confirms our hs-CRP findings and suggests that TDF/FTC exposure has a minimal effect on this inflammatory pathway. However, these findings contrast with previous in vitro findings where TFV exposure resulted in a dose-dependent stimulation of IL-6, TNF-α and IL-10 in rat macrophages [12,13,14,42] and inhibition of IL-10 in human PBMCs [15]. Additionally, these findings are also distinct from recent data derived from topical TFV exposure where this drug decreased IL-2 and TNF-α in vaginal secretions [17] and IL-6 and IL-8 gene expression in rectal tissue biopsies [18].…”

Section: Discussioncontrasting

confidence: 98%

“…Assessing this relationship was a pre-specified secondary endpoint of this pharmacokinetic study. This novel biologic finding in vivo extends previous in vitro observations where TFV exposure resulted in immunomodulation in macrophages and lymphocytes [12,13,14,15,16]. Additional research is needed to replicate our findings in larger populations and to elucidate the clinical implications of decreased immune activation in HIV-negative persons receiving TDF/FTC therapy.…”

Section: Discussionsupporting

confidence: 81%

“…In addition to its inhibition of reverse transcriptase to elicit antiviral activity, TFV has diverse immunomodulatory effects in various human and animal immune cell lines. Previous in vitro research has identified an anti-inflammatory effect of TFV and other acyclic nucleoside phosphonates in macrophages, lymphocytes and murine hepatocytes [12,13,14], while other studies have reported a pro-inflammatory effect [12,15,16]. Recent studies have also associated immune quiescence with topical TFV exposure in the murine vagina and the human rectum [17,18].…”

Section: Introductionmentioning

confidence: 99%

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Reduced Immune Activation During Tenofovir–Emtricitabine Therapy in HIV-Negative Individuals

Castillo‐Mancilla

Meditz²,

Wilson

et al. 2015

JAIDS Journal of Acquired Immune Deficiency Syndromes

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Background Elevated immune activation is associated with an increased risk of HIV acquisition. Tenofovir (TFV) has immunomodulatory properties in vitro, but how this extends in vivo remains unknown. Methods HIV-negative adults received daily co-formulated tenofovir-disoproxil-fumarate (TDF) 300 mg/emtricitabine (FTC) 200 mg for 30 days followed by a 30-day washout. Markers of T-cell activation, inflammation and cytokines were measured before drug and on days 30 (on drug) and 60 (30-day washout). Data were analyzed using one-way ANOVA/pairwise comparisons. Intracellular disposition of TFV-diphosphate (TFV-DP) and FTC-triphosphate (FTC-TP) in CD4+ and CD8+ T-cells and monocytes was characterized, and the relationship with immune activation was evaluated using Pearson correlation coefficient. Results T-cell activation was available in 19 participants. CD38/HLA-DR co-expression on CD8+ T-cells decreased from baseline to day 30 (3.97 vs. 2.71%;P=0.03) and day 60 (3.97 vs. 2.41%;P=0.008). Soluble CD27 decreased from baseline to day 60 (184.1 vs. 168.4 pg/ml;P=0.001). Cytokines and inflammation markers were not significantly different. TFV-DP and FTC-TP were approximately 4-fold higher in monocytes vs. CD4+ and CD8+ T-cells, but neither correlated with activation markers. Conclusions TDF/FTC therapy was associated with decreased T-cell activation in HIV-negative adults, which could contribute to the antiviral effect of pre-exposure prophylaxis.

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Section: Discussioncontrasting

confidence: 98%

Section: Discussionsupporting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

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Reduced Immune Activation During Tenofovir–Emtricitabine Therapy in HIV-Negative Individuals

Castillo‐Mancilla

Meditz²,

Wilson

et al. 2015

JAIDS Journal of Acquired Immune Deficiency Syndromes

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“…2). Beyond their antimetabolite activity, NAs have been described to exert immunostimulatory effects in vitro [4,5]. However, it is unclear if and to what extent these effects contribute to their antiviral potency.…”

Section: Mechanism Of Actionmentioning

confidence: 99%

Antiviral Therapy of Chronic Hepatitis B

Bömmel

Berg²

2014

Intervirology

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Since the licensing of lamivudine in 1999, the treatment of chronic hepatitis B has been revolutionized by the introduction of oral nucleoside and nucleotide analogues (NAs), which act as inhibitors of the HBV polymerase. The effectiveness of the first of these substances was limited by incomplete response and resistance development in many patients, but today, highly potent substances are available that make a reliable and durable suppression of HBV replication, a reduction of necroinflammatory activity in the liver, and even a reversion of liver fibrosis achievable for almost all patients. Beyond that, NA treatment can prevent the development of hepatocellular carcinoma in many patients. HBeAg seroconversion appears in approximately 50% of all HBeAg-positive patients during NA treatment. However, the ideal treatment endpoint, the serologic loss of HBsAg, remains a rare event almost exclusively achievable for HBeAg-positive patients. After cessation of the treatment, HBV replication tends to relapse in most patients, which is why the duration of NA treatment is indefinite. Future treatment strategies should aim at tailoring individual NA treatment regimens to increase HBs loss rates and optimize treatment duration.

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“…subsequent amelioration of inflammation. However, recent studies revealed that these NUCs modulate tumor necrosis factor-a (TNF-a) expression (Zídek et al, 1999;Biswas et al, 2014), NO production (Zídek et al, 2000;Kostecká et al, 2012), and neovascularization (Mizutani et al, 2015), all of which participate in pathogenesis of liver cirrhosis and portal hypertension. If NUCs exert independent benefits in reversing liver fibrosis and portal hypertension, it may be possible to apply them to patients with nonviral chronic liver diseases.…”

Section: Introductionmentioning

confidence: 99%

Nucleos(t)ide Analogs Do Not Independently Influence Hepatic Fibrosis and Portal Hypertension beyond Viral Suppression in CBDL-Induced Cirrhotic Rat

Hsieh

Chang

Chuang

et al. 2018

J Pharmacol Exp Ther

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Chronic hepatitis is the major cause of liver cirrhosis and portal hypertension. Several factors affect portal pressure, including liver fibrosis, splanchnic vasodilatation, and pathologic angiogenesis. Nucleos(t)ide analogs (NUCs), the oral antiviral agents, effectively attenuate chronic hepatitis B-related liver cirrhosis and portal hypertension via viral suppression and alleviation of hepatitis. On the other hand, NUCs affect tumor necrosis factor (TNF)-, vascular endothelial growth factor (VEGF), and nitric oxide, which participate in fibrogenesis, vasodilatation, and angiogenesis. However, whether NUCs independently influence liver fibrosis and portal hypertension beyond viral suppression is unknown. This study thus aimed to evaluate the influences of three frequently used NUCs in rats with nonviral cirrhosis. Male Sprague-Dawley rats received common bile duct ligation (CBDL) to induce cholestatic cirrhosis and portal hypertension. The rats were randomly allocated into four groups, treated by mouth with lamivudine (30 mg/kg per day), entecavir (0.09 mg/kg per day), tenofovir (50 mg/kg per day), or distilled water (vehicle control) from the 15th day after CBDL. On the 29th day, liver cirrhosis- and portal hypertension-related parameters were evaluated. The results showed that chronic NUCs treatment did not affect hemodynamic parameters, plasma TNF- concentration, and hepatic fibrogenesis protein expressions in rats with nonviral cirrhosis. Though the mesenteric VEGF receptor 2 phosphorylation was downregulated in NUCs-treated groups, the splanchnic angiogenesis was not influenced. In conclusion, lamivudine, entecavir, and tenofovir had no additional effects on liver cirrhosis and portal hypertension in rats with nonviral cirrhosis.

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Differential effects of acyclic nucleoside phosphonates on nitric oxide and cytokines in rat hepatocytes and macrophages

Cited by 10 publications

References 32 publications

Reduced Immune Activation During Tenofovir–Emtricitabine Therapy in HIV-Negative Individuals

Reduced Immune Activation During Tenofovir–Emtricitabine Therapy in HIV-Negative Individuals

Antiviral Therapy of Chronic Hepatitis B

Nucleos(t)ide Analogs Do Not Independently Influence Hepatic Fibrosis and Portal Hypertension beyond Viral Suppression in CBDL-Induced Cirrhotic Rat

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