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

Abstract

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.

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

“…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.…”

Effects of the MAPK pathway and the expression of CAR in a murine model of viral myocarditis

“…A recent study has shown an association between higher apoptosis rates and a decrease in contractile function in VMC (17) and the relationship between p38 MAPK activation cell apoptosis induction is known (17). Finally, SB203580 inhibits p38 MAPK by reducing downstream activation of MAPKAP kinase-2 and kinase-3, which effectively reduces the signal transduction pathway induced by inflammatory factors such as IL-1β and TNF-α (18). …”

Interleukin-17A Aggravates Middle Ear Injury Induced by Streptococcus pneumoniae through the p38 Mitogen-Activated Protein Kinase Signaling Pathway

“…Similarly, our previous studies have demonstrated that IL-17A induces neutrophil recruitment through the p38 MAPK signaling pathway rather than the ERK or JNK signaling pathway during AOM (23). Furthermore, studies have shown that activation of p38 MAPK exacerbates acute lung injury and dengue virus-induced liver injury (45,46). Therefore, we wondered whether IL-17A-related pathogenic effects were also dependent on the p38 MAPK signaling pathway during AOM.…”