NF-κB-Mediated Modulation of Inducible Nitric Oxide Synthase Activity Controls Induction of the Epstein-Barr Virus Productive Cycle by Transforming Growth Factor Beta 1

Abstract

Transforming growth factor beta 1 (TGF-␤1) signal transduction has been implicated in many secondmessenger pathways, including the NF-B pathway. We provide evidence of a novel TGF-␤1-mediated pathway that leads to extracellular signal-regulated kinase (ERK) 1/2 phosphorylation, which in turn induces expression of an Epstein-Barr virus (EBV) protein, ZEBRA, that is responsible for the induction of the viral lytic cycle. This pathway includes two unexpected steps, both of which are required to control ERK 1/2 phosphorylation: first, a quick and transient activation of NF-B, and second, downregulation of inducible nitric oxide synthase (iNOS) activity that requires the participation of NF-B activity. Although necessary, NF-B alone is not sufficient to produce downregulation of iNOS, suggesting that another uncharacterized event(s) is involved in this pathway. Dissection of the steps involved in the switch from the EBV latent cycle to the lytic cycle will be important to understand how virus-host relationships modulate the innate immune system.

Regulation of the latent-lytic switch in Epstein–Barr virus

“…Conversely, inhibitors of these kinases reduce the effectiveness of several lytic-inducing stimuli [13,28,29,62,66]. NF-κB activation is also required for induction via BCR engagement and TGF-β, likely through effects on MAPKs [62,67]. Once expressed, Z can bind to and activate its own promoter (Fig.…”

“…TGF-β, a cytokine secreted by T cells, can induce EBV reactivation via activating BZLF1 gene expression in some type I BL cell lines [12,13,67]. This effect is mediated in large part via binding of TGF-β1 to the TGF-β type II receptor (TβRII), thereby triggering heterodimerization and transphosphorylation of the TGF-β type I receptor (TβRI) which then phosphorylates Smad2 and Smad3, which then complex with Smad4 (Fig.…”

Over-production of nitric oxide by oxidative stress-induced activation of the TGF-β1/PI3K/Akt pathway in mesangial cells cultured in high glucose

“…This result suggests that the TGF-β1/PI3K pathway participates in iNOS generation in MCs under high glucose conditions. TGF-β1 is required for NF-kappaB-mediated modulation of iNOS activity when controlling the induction of the Epstein-Barr virus replication cycle [40] . A report showed that TGF-β1 stimulates NO production in astrocytes by recruiting distinct cell subpopulations [41] .…”

Inducible nitric oxide synthase (iNOS) regulatory region variation in non-human primates

“…In the list of conserved RE/TF binding sites across these species of NHP, NF-κB is the most well-studied transcription factor known an important role in regulation of iNOS expression (Uffort et al, 2009; Chan et al, 2001; Jaramillo et al, 2003; Oussaief et al, 2011; Kelleher et al, 2007; Feng et al, 2002). Previous studies have shown that NF-κB modulates iNOS expression during various viral, bacterial, and parasitic infections (Oussaief et al, 2011; Chan et al, 2001; Jaramillo et al, 2003).…”

“…Previous studies have shown that NF-κB modulates iNOS expression during various viral, bacterial, and parasitic infections (Oussaief et al, 2011; Chan et al, 2001; Jaramillo et al, 2003). It has also been shown that interference in the NF-κB -dependent regulation of iNOS expression is part of the pathogenic mechanism for Helicobacter pylori (Kim et al, 2003); a similar mechanism may be involved in the pathogenesis of other infectious diseases (e.g., Mycobacterium tuberculosis ).…”