JNK1/2 inhibitor reduces dengue virus-induced liver injury

Sreekanth, Gopinathan Pillai; Chuncharunee, Aporn; Cheunsuchon, Boonyarit; Noisakran, Sansanee; Yenchitsomanus, Pa‐thai; Limjindaporn, Thawornchai

doi:10.1016/j.antiviral.2017.02.003

Cited by 22 publications

(24 citation statements)

References 72 publications

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“…At early infection, apoptosis can serve as an antiviral strategy, but apoptosis induced at late stage of infection may facilitate virus spreading and immune evasion. Therapeutical manipulation of JNK may be a viable approach to control viral replication or tissue damage associated with infection, as shown in a recent study for dengue virus 46 . Also, vaccine strains that induced reduced apoptosis may be desirable, because viral epitopes are displayed longer for immune stimulation, favoring activation of cell-mediated immune response.…”

Section: Discussionmentioning

confidence: 98%

Activation of the c-Jun NH2-terminal kinase pathway by coronavirus infectious bronchitis virus promotes apoptosis independently of c-Jun

Fung

Liu

2017

Cell Death Dis

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Mitogen-activated protein kinases (MAPKs) are conserved protein kinases that regulate a variety of important cellular signaling pathways. Among them, c-Jun N-terminal kinases (JNK) are known to be activated by various environmental stresses including virus infections. Previously, activation of the JNK pathway has been detected in cells infected with several coronaviruses. However, detailed characterization of the pathway as well as its implication in host–virus interactions has not been fully investigated. Here we report that the JNK pathway was activated in cells infected with the avian coronavirus infectious bronchitis virus (IBV). Of the two known upstream MAPK kinases (MKK), MKK7, but not MKK4, was shown to be responsible for IBV-induced JNK activation. Moreover, knockdown and overexpression experiments demonstrated that JNK served as a pro-apoptotic protein during IBV infection. Interestingly, pro-apoptotic activity of JNK was not mediated via c-Jun, but involved modulation of the anti-apoptotic protein B-cell lymphoma 2 (Bcl2). Taken together, JNK constitutes an important aspect of coronavirus–host interaction, along with other MAPKs.

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Section: Discussionmentioning

confidence: 98%

Activation of the c-Jun NH2-terminal kinase pathway by coronavirus infectious bronchitis virus promotes apoptosis independently of c-Jun

Fung

Liu

2017

Cell Death Dis

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“…In patients with hepatomegaly, viral antigens are present in hepatocytes as well as in Kupfer cells [ 93 , 94 ]. An ensuing consequence of hepatocyte infection by DENV is cellular apoptosis, which has been demonstrated in in vivo as well as in vitro experiments [ 95 , 96 ]. Both the intrinsic and extrinsic apoptotic pathways are activated in response to DENV infection [ 97 ].…”

Section: S1p and Viral Infectionsmentioning

confidence: 99%

Divergent Role of Sphingosine 1-Phosphate in Liver Health and Disease

Kleuser

2018

IJMS

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Two decades ago, sphingosine 1-phosphate (S1P) was discovered as a novel bioactive molecule that regulates a variety of cellular functions. The plethora of S1P-mediated effects is due to the fact that the sphingolipid not only modulates intracellular functions but also acts as a ligand of G protein-coupled receptors after secretion into the extracellular environment. In the plasma, S1P is found in high concentrations, modulating immune cell trafficking and vascular endothelial integrity. The liver is engaged in modulating the plasma S1P content, as it produces apolipoprotein M, which is a chaperone for the S1P transport. Moreover, the liver plays a substantial role in glucose and lipid homeostasis. A dysfunction of glucose and lipid metabolism is connected with the development of liver diseases such as hepatic insulin resistance, non-alcoholic fatty liver disease, or liver fibrosis. Recent studies indicate that S1P is involved in liver pathophysiology and contributes to the development of liver diseases. In this review, the current state of knowledge about S1P and its signaling in the liver is summarized with a specific focus on the dysregulation of S1P signaling in obesity-mediated liver diseases. Thus, the modulation of S1P signaling can be considered as a potential therapeutic target for the treatment of hepatic diseases.

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“…Viral antigens were detected in hepatocytes and Kuppfer cells in patients with hepatomegaly and raising level of serum transaminases [ 8 – 12 ]. BALB/c mouse models of DENV infection [ 13 – 15 ] revealed that high levels of apoptosis were found in livers with high viral load [ 13 , 14 , 16 ]. World Health Organization (WHO) guideline suggested organ injury as one of the criteria for determining severity of DENV disease [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

RNAi screen reveals a role of SPHK2 in dengue virus–mediated apoptosis in hepatic cell lines

et al. 2017

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Hepatic dysfunction is a feature of dengue virus (DENV) infection. Hepatic biopsy specimens obtained from fatal cases of DENV infection show apoptosis, which relates to the pathogenesis of DENV infection. However, how DENV induced liver injury is not fully understood. In this study, we aim to identify the factors that influence cell death by employing an apoptosis-related siRNA library screening. Our results show the effect of 558 gene silencing on caspase 3-mediated apoptosis in DENV-infected Huh7 cells. The majority of genes that contributed to apoptosis were the apoptosis-related kinase enzymes. Tumor necrosis factor superfamily member 12 (TNFSF12), and sphingosine kinase 2 (SPHK2), were selected as the candidate genes to further validate their influences on DENV-induced apoptosis. Transfection of siRNA targeting SPHK2 but not TNFSF12 genes reduced apoptosis determined by Annexin V/PI staining. Knockdown of SPHK2 did not reduce caspase 8 activity; however, did significantly reduce caspase 9 activity, suggesting its involvement of SPHK2 in the intrinsic pathway of apoptosis. Treatment of ABC294649, an inhibitor of SPHK2, reduced the caspase 3 activity, suggesting the involvement of its kinase activity in apoptosis. Knockdown of SPHK2 significantly reduced caspase 3 activity not only in DENV-infected Huh7 cells but also in DENV-infected HepG2 cells. Our results were consistent across all of the four serotypes of DENV infection, which supports the pro-apoptotic role of SPHK2 in DENV-infected liver cells.

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JNK1/2 inhibitor reduces dengue virus-induced liver injury

Cited by 22 publications

References 72 publications

Activation of the c-Jun NH2-terminal kinase pathway by coronavirus infectious bronchitis virus promotes apoptosis independently of c-Jun

Activation of the c-Jun NH2-terminal kinase pathway by coronavirus infectious bronchitis virus promotes apoptosis independently of c-Jun

Divergent Role of Sphingosine 1-Phosphate in Liver Health and Disease

RNAi screen reveals a role of SPHK2 in dengue virus–mediated apoptosis in hepatic cell lines

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