Inhibition of p38MAPK and CD137 signaling reduce dengue virus-induced TNF-α secretion and apoptosis

Abstract

BackgroundHepatic injury in dengue virus (DENV) infection is authenticated by hepatomegaly and an upsurge in transaminase levels. DENV replicates in hepatocytes and causes hepatocyte apoptosis both in vitro and in vivo. Understanding the molecular mechanisms of DENV-induced hepatic injury could facilitate the development of alternate chemotherapeutic agents and improved therapies.FindingsThe p38 mitogen-activated protein kinase (MAPK) participates in both apoptosis-related signaling and pro- inflammatory cytokine production. The role of p38 MAPK in DENV-infected HepG2 cells was examined using RNA interference. The results showed that DENV infection activated p38 MAPK and induced apoptosis. The p38 MAPK activation and TNF-α production were controlled by p38 MAPK and CD137 signaling in DENV-infected HepG2 cells as activated p38 MAPK, TNF-α and apoptosis were significantly decreased in p38 MAPK and CD137 depleted DENV-infected HepG2 cells. Addition of exogenous TNF-α to p38 MAPK depleted DENV-infected HepG2 cells restored DENV-induced apoptosis in HepG2 cells.ConclusionDENV induces CD137 signaling to enhance apoptosis by increasing TNF-α production via activation of p38 MAPK.

Role of ERK1/2 signaling in dengue virus-induced liver injury

“…Transaminase levels are increased in DENV-infected patients (Halstead, 1988;Kuo et al, 1992;Souza et al, 2004) and in a murine model of DENV infection (Barth et al, 2006;Chen et al, 2004;Franca et al, 2010;Paes et al, 2005Paes et al, , 2009). Apoptosis of hepatic cells, which may be related to the pathogenesis of DSS, has been observed both in vitro and in vivo (Couvelard et al, 1999;El-Bacha et al, 2007;Huerre et al, 2001;Limonta et al, 2007;Lin et al, 2008;Marianneau et al, 1998;Morchang et al, 2011;Nagila et al, 2011Nagila et al, , 2013Netsawang et al, 2010;Thongtan et al, 2004). DENV infection promotes apoptosis in the hepatoma cell line, HepG2, partly through the induction of TRAIL, a member of the death receptor pathway (Matsuda et al, 2005).…”

“…DENV infection promotes apoptosis in the hepatoma cell line, HepG2, partly through the induction of TRAIL, a member of the death receptor pathway (Matsuda et al, 2005). TNF-␣ and Fas signaling also contribute to DENV-mediated apoptosis (Limjindaporn et al, 2007;Nagila et al, 2013). The mitochondria of DENV-infected HepG2 cells exhibit functional and morphological defects, suggesting activation of the mitochondrial cell death pathway (El-Bacha et al, 2007).…”

“…Following DENV infection, phosphorylated p38 MAPK is induced (Ceballos-Olvera et al, 2009;Huerta-Zepeda et al, 2008;Lee et al, 2008;Nagila et al, 2013). Inhibition of p38 MAPK reduces DENV-mediated apoptosis of HepG2 cell line (Nagila et al, 2013).…”

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

“…However, we detected slightly more 282 viruses in the SB203580 treated animals compared to control AG129 mice. Recently, p38 MAPK inhibition has been described 284 to limit the apoptosis of infected cells(Nagila et al, 2013). In that285 context, delaying apoptosis or inflammation in vivo may favor 286 more viruses to be produced after 5 days of therapy.…”

Tumor necrosis factor receptor superfamily member 9 is upregulated in the endothelium and tumor cells in melanoma brain metastasis

“…[21] Although it has been demonstrated that HIF1α-related TNFRSF9 upregulation is beneficial for the survival of hematopoietic cells, it can induce cellular apoptosis in other cell types such as liver or tumor cells. [22][23][24] This might at least partly explain why severe liver toxicity occurred in the first clinical studies targeting TNFRSF9 in humans. [25] Whether enhanced TNFRSF9 expression in perinecrotic areas in melanoma brain metastasis is beneficial or detrimental to the tumor remains an open question.…”