(E) Quantification of results in D. ** P < 0.01 and # P < 0.05 for Student's t-test versus Mock + H2O and HSV-1 + H2O groups, respectively. These observations collectively suggest that ERK MAPK pathway also contributes to HSV-1-induced KSHV replication. 4. Discussion Deregulation of cellular signal

pathways is involved in the infection process and replication of many viruses and is also likely to contribute to pathogenesis and viral oncogenesis. Many signal pathways, such as JAK/STAT, PI3K/AKT, MAPK, protein kinase C (PKC), nuclear factor kappa B (NF-κB) and Notch have been shown to participate in KSHV infection, replication and angiogenesis [5, 23–29]. In this study, we did not observe any evidence that JAK1/STAT3 and JAK1/STAT6, which were the traditional pathways activated by IL-10/IL-10R and IL-4/IL-4R, were involved in KSHV replication by HSV-1, but GSI-IX concentration PI3K/AKT and ERK MAPK pathways induced by IL-10 and IL-4 contributed to this replication. PI3K/AKT signaling pathway plays an important role in cell growth and survival. PI3K is a heterodimer composed of a catalytic subunit p110 and an adaptor/regulatory subunit p85 [30]. PI3K activation leads to AKT activation. AKT is a critical regulator of PI3K-mediated cell survival and AKT phosphorylates and inactivates several proapoptotic proteins including GSK-3β [31]. PTEN is a negative regulator of PI3K/AKT pathway [32]. PTEN counters the effects

of PI3K and inhibits AKT. PTEN is inactivated by phosphorylation, leading to the activation of AKT. With respect to KSHV and activation of PI3K/AKT, many studies focused on viral G protein-coupled receptor (vGPCR) selleckchem and K1 genes. PI3K/AKT pathway played an essential role in vGPCR sarcomagenesis [33, 34]. The activation of PI3K/AKT pathway by K1 promoted cell survival

and immortalization and might contribute to KSHV-associated tumorigenesis [35, 36]. In this study, we have provided direct experimental evidence that not only suppression of PI3K/AKT signal pathway, but also overexpression of PTEN and activation of GSK-3β inhibited HSV-1-induced KSHV replication, implying Y-27632 complicated functions of PI3K/AKT pathway not only in viral oncogenesis. Interestingly, a report showed that inhibition of PI3K pathway did not impair induction of KSHV lytic replication by metabolic end products of Gram-negative anaerobic bacteria [37]. Another study demonstrated that inhibition of PI3K/AKT pathway enhanced KSHV and murine gammaherpesvirus-68 (MHV-68) lytic replication [38]. We speculated that there were at least three reasons: (1) different inducers and cell lines may exhibit different mechanisms and effects, (2) PI3K and AKT both have a wide range of cellular targets and show complicated functions dependent on the context, and (3) we also simultaneously used dominant negative protein expression plasmids of this pathway, while Peng et al. just only used chemical inhibitors.

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