Differential utilization of NF-kappaB RELA and RELB in response to extracellular versus intracellular polyIC stimulation in HT1080 cells

Here, we studied an intracellular dsRNA pathway in the human fibrosarcoma cell line HT1080, which is distinct from the TLR3-mediated extracellular dsRNA pathway. Particularly, the NF-kB subunits RELA and RELB were differentially utilized by these two dsRNA signaling pathways. In TLR3-mediated dsRNA signaling, siRNA knock-down studies suggested a limited role for RELA on regulation of interferon beta and other cytokines whereas RELB appeared to have a negative regulatory role. By contrast, intracellular dsRNA signaling was dependent on RELA, but not RELB.Our study suggests that extracellular and intracellular dsRNA signaling pathways may utilize different NF-kB members, and particularly the differential utilization of RELB may be a key mechanism for powerful inductions of NF-kB regulated genes in the intracellular dsRNA signaling pathway.Pattern recognition receptors (PRRs) are key players in host innate immune response against microbial pathogens. In order to launch effective defense mechanisms in response to viral infections, a number of cellular sensors that recognize universal components common to many viruses have been characterized. Double-stranded RNA (dsRNA) is one of the components that mammalian cells have developed several different receptors for since most viruses produce dsRNA during replication [1-3].Interferon-inducible double-stranded RNA activated protein kinase (PKR) has long been studied as an intracellular sensor for viral dsRNA. PKR was initially characterized to participate in the mechanism that shuts down cellular translation to suppress viral replication and is now believed to be involved in a wide range of other cellular responses to viral infection [4]. Toll-like receptor 3 (TLR3) has been considered to be essential for mediating NF-kB-inducible gene responses to polyIC, a synthetic analogue of viral dsRNA [5], but there has yet been any strong evidence of physical interaction between TLR3 and viral dsRNA. The precise cellular location of TL