The family of interferon (IFN) regulatory factors (IRFs) encodes DNA-binding transcription factors, some of which function as modulators of virus-induced signaling. The IRF-3 gene is constitutively expressed in many tissues and cell types, and neither virus infection nor IFN treatment enhances its transcription. In infected cells, however, IRF-3 protein is phosphorylated at the carboxyl terminus, which facilitates its binding to the CBP͞p300 coactivator.

No abstract

IFNs1 are a family of natural proteins serving as part of the defense systems against infections. Cells can produce IFNs in response to virus infection, and the newly synthesized IFNs are secreted extracelluarly, bind to IFN receptors, and activate the Jak-Stat signaling pathway that leads to the stimulation of expression of cellular genes generally called ISGs (1-3). Some of these genes encode proteins that can inhibit viral replication, thus conferring the antiviral state to the cells (3). While the molecular mechanism involved in the induction of IFN and ISG genes has been studied in great detail in vitro, it is largely unknown how much this system is affected by other stress factors. Of special concern is the potential impact of the bacterial infection on this system because concomitant infection with both bacteria and virus is a common clinical situation.LPS is the major component of the outer membrane of Gramnegative bacteria (4). Through activation of the target cells such as macrophages and B cells, LPS induces innate immune response and expression of cytokine genes which include IL-1, IFNB, and TNF␣ (5, 6). These cytokines are responsible for most of the biological effects of LPS and deregulated production of these cytokines results in the generalized inflammation or endotoxic shock. The signal transduction pathway for LPS is initiated by its binding to LBP (LPS binding protein) (7), an acute phase reactant produced by the liver, followed by the binding to CD14, a glycosylphosphatidylinositol-anchored membrane protein (8, 9) and Toll-like receptor (TLR2) (10). This receptor is activated by LPS and the response depends on the binding of LPS to LBP and is enhanced by CD14. After binding to the receptor, LPS activates a number of tyrosine and serine kinases, including Raf-1, p42 and p44 isoforms of the MAP kinase, the p38 kinase, c-Jun kinase, ceramide activated kinase (CAK) and CD14 receptor-coupled kinase p56 lyn (11-13), with consequent activation of nuclear transcription factors such as NF-B, Stat1 (signal transducer and activator of transcription), Stat3, and NF-IL6 (C/EBP) (14 -18). LPS was also shown to activate nuclear factors binding to the interferon stimulation responsible element although the identity of these factors has not been elucidated (19,20). Furthermore, functional cooperation between LPS and IFNs, especially IFN␥, was shown to result in expression of a set of pro-inflammatory genes (21,22). Considering that IFNA and IFNB promoters contain cis-elements which are highly homologous to the interferon stimulation responsible element, these findings indicate that LPS may potentially modulate the expression of IFN genes.The signal transduction pathway leading to the induction of IFN genes expression in virus-infected cells is largely unknown. The analysis of the virus responsive element (VRE) of both IFNA and IFNB promoters has identified highly conserved purine-rich sequence repeats that were shown to bind the transcription factors of the IRF family (23-28). In addition, IFNB gene promoter ...