Modulation of inflammation and pathology during dengue virus infection by p38 MAPK inhibitor SB203580

Fu, Yilong; Yip, Andy M.; Seah, Peck Gee; Blasco, Francesca; Shi, Pei–Yong; Hervé, Maxime

doi:10.1016/j.antiviral.2014.08.004

Cited by 36 publications

(31 citation statements)

References 41 publications

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“…Since the inhibitor did not reduce p38 MAPK phosphorylation, there is a possibility that SB203580 may be acting directly on downstream molecules as well as p38 MAPK. Our study supports the previous studies, as p38 MAPK plays an important role in the induction of pro-inflammatory cytokine TNF-α during DENV infection [ 20 ] and modulation of inflammation and pathology in DENV infected mice by p38 MAPK inhibitor, SB203580 [ 54 ]. However, we open up the path to further investigate the downstream signals towards MAPK pathway, which is very important to better understand the pathogenesis of DENV infection.…”

Section: Discussionsupporting

confidence: 92%

“…Recently, SB203580 has been shown to improve the clinical manifestations and systemic inflammation in an animal model of DENV infection. This interesting study shows oral administration of SB203580 in immuno-competent AG129 mice, decreases the circulation of pro-inflammatory cytokines (TNF-α, IL-6 and MMP-9) and reduces the leakage resulting a better survival rate [ 54 ]. But interestingly, there is neither in vitro nor in vivo study which shows the mechanism by which SB203580 treatment modulates apoptosis in DENV infection.…”

Section: Discussionmentioning

confidence: 99%

“…This study shows that oral administration of SB203580 decreased the circulation of pro-inflammatory cytokines. However, the high viral load was still presented in livers of infected mice [ 54 ]. In a recent study of intra-cerebral inoculation of DENV in Balb/c mice also shows viremia and the induction of host immune response with organ damage including liver.…”

Section: Introductionmentioning

confidence: 99%

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SB203580 Modulates p38 MAPK Signaling and Dengue Virus-Induced Liver Injury by Reducing MAPKAPK2, HSP27, and ATF2 Phosphorylation

et al. 2016

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Dengue virus (DENV) infection causes organ injuries, and the liver is one of the most important sites of DENV infection, where viral replication generates a high viral load. The molecular mechanism of DENV-induced liver injury is still under investigation. The mitogen activated protein kinases (MAPKs), including p38 MAPK, have roles in the hepatic cell apoptosis induced by DENV. However, the in vivo role of p38 MAPK in DENV-induced liver injury is not fully understood. In this study, we investigated the role of SB203580, a p38 MAPK inhibitor, in a mouse model of DENV infection. Both the hematological parameters, leucopenia and thrombocytopenia, were improved by SB203580 treatment and liver transaminases and histopathology were also improved. We used a real-time PCR microarray to profile the expression of apoptosis-related genes. Tumor necrosis factor α, caspase 9, caspase 8, and caspase 3 proteins were significantly lower in the SB203580-treated DENV-infected mice than that in the infected control mice. Increased expressions of cytokines including TNF-α, IL-6 and IL-10, and chemokines including RANTES and IP-10 in DENV infection were reduced by SB203580 treatment. DENV infection induced the phosphorylation of p38MAPK, and its downstream signals including MAPKAPK2, HSP27 and ATF-2. SB203580 treatment did not decrease the phosphorylation of p38 MAPK, but it significantly reduced the phosphorylation of MAPKAPK2, HSP27, and ATF2. Therefore, SB203580 modulates the downstream signals to p38 MAPK and reduces DENV-induced liver injury.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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SB203580 Modulates p38 MAPK Signaling and Dengue Virus-Induced Liver Injury by Reducing MAPKAPK2, HSP27, and ATF2 Phosphorylation

et al. 2016

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“…Since a number of p38MAPK inhibitors are in clinical development for treating diseases such as arthritis and chronic obstructive pulmonary disease (Norman, 2015), our study warrants further evaluation of the effects of these inhibitors in other ZIKV-infected in vitro and in vivo models as well as in human subjects, which may lead to a novel therapy for ZIKV-induced pathological changes. This possibility is supported by two related studies showing that administration of p38MAPK inhibitor limits inflammation, prevents hematocrit rise, lymphopenia and liver injury, and improves survival rate in mice infected by DENV (Fu et al, 2014; Sreekanth et al, 2016), another flavivirus that induces overlapped but distinct cellular responses with ZIKV.…”

Section: Discussionmentioning

confidence: 81%

p38MAPK plays a critical role in induction of a pro-inflammatory phenotype of retinal Müller cells following Zika virus infection

et al. 2017

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Zika virus (ZIKV) infection has been associated with ocular abnormalities such as chorioretinal atrophy, optic nerve abnormalities, posterior uveitis and idiopathic maculopathy. Yet our knowledge about ZIKV infection in retinal cells and its potential contribution to retinal pathology is still very limited. Here we found that primary Müller cells, the principal glial cells in the retina, expressed a high level of ZIKV entry cofactor AXL gene and were highly permissive to ZIKV infection. In addition, ZIKV-infected Müller cells exhibited a pro-inflammatory phenotype and produced many inflammatory and growth factors. While a number of inflammatory signaling pathways such as ERK, p38MAPK, NF-κB, JAK/STAT3 and endoplasmic reticulum stress were activated after ZIKV infection, inhibition of p38MAPK after ZIKV infection most effectively blocked ZIKV-induced inflammatory and growth molecules. In comparison to ZIKV, Dengue virus (DENV), another Flavivirus infected Müller cells more efficiently but induced much lower pro-inflammatory responses. These data suggest that Müller cells play an important role in ZIKV-induced ocular pathology by induction of inflammatory and growth factors in which the p38MAPK pathway has a central role. Blocking p38MAPK may provide a novel approach to control ZIKV-induced ocular inflammation.

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“…p38 MAP kinases have been experimentally validated to act as therapeutic targets for joint diseases, septic shock (Lee et al, 1999), inflammatory diseases (Kumar et al, 2003;Saklatvala, 2004), and myocardial injury (Gao et al, 2002). Recently, it was demonstrated that inhibition of p38 MAP kinase proved beneficial to reduce disease symptoms in dengue hemorrhagic fever (Fu et al, 2014), so inhibiting phosphorylation at this site might be important for viral activity inhibition in Ebola.…”

Section: Analysis Of Solvent Accessibility and Structural Informationmentioning

confidence: 99%

In silico assessment of phosphorylation and O-β-GlcNAcylation sites in human NPC1 protein critical for Ebola virus entry

Basharat¹,

Yasmin²

2015

Infection, Genetics and Evolution

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Modulation of inflammation and pathology during dengue virus infection by p38 MAPK inhibitor SB203580

Cited by 36 publications

References 41 publications

SB203580 Modulates p38 MAPK Signaling and Dengue Virus-Induced Liver Injury by Reducing MAPKAPK2, HSP27, and ATF2 Phosphorylation

SB203580 Modulates p38 MAPK Signaling and Dengue Virus-Induced Liver Injury by Reducing MAPKAPK2, HSP27, and ATF2 Phosphorylation

p38MAPK plays a critical role in induction of a pro-inflammatory phenotype of retinal Müller cells following Zika virus infection

In silico assessment of phosphorylation and O-β-GlcNAcylation sites in human NPC1 protein critical for Ebola virus entry

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