Taken together, these data indicate that CXCL10 induction during both early HCV infection and PRR-specific stimulation is predominantly mediated by NF-��B and IRF3, with minor negative modulation by AP-1 and C/EBP-�� occurring (Table 1). Although AP-1 and C/EBP-�� are typically considered positive regulators of gene expression, instances of negative regulation have also been selleck compound documented. C/EBP-�� has been shown to negatively regulate transcription of the tumor suppressor microRNA miR-145 in breast cancer cells (55). There is also evidence that C/EBP-�� inhibits collagen synthesis in fibroblasts in response to type II IFN and extracellular signal-regulated kinase 1/2 (ERK1/2) MAP kinase signaling (56).

Similarly, Fos/Jun AP-1 heterodimers have been shown to negatively regulate transcription of the steroidogenic enzyme CYP17 following ERK1/2 activation (57), while IL-4 is negatively regulated by the JunD AP-1 homodimer (30). Given the vast array of subunits that can comprise AP-1, other less well studied heterodimers may also negatively regulate the induction of target genes. Different heterodimers could also be activated in response to different stimuli. This could potentially explain the differential effect of AP-1 on CXCL10 induction during treatment with PRR-specific PAMPs (negative regulation) in comparison to that during early HCV infection (no significant regulatory effect). Induction of CXCL10 in hepatocytes may also be influenced by transcription factors not surveyed in our study. For example, type II IFN (i.e.

, IFN-��) signaling leads to the formation of STAT1 homodimers that bind to gamma interferon activation site (GAS) elements in ISGs (8). Type II IFN is the canonical inducer of CXCL10 produced by proinflammatory immune effector cells, and GAS elements have recently been identified within the CXCL10 promoter (58, 59). However, production of type II IFNs has been documented only in professional immune cells, and we previously GSK-3 showed that this cytokine did not contribute to CXCL10 induction in HCV-infected PHH cultures that were depleted of immune effector and nonparenchymal cells (9, 44). This suggests that type II IFN does not contribute to CXCL10 induction in the hepatocyte monocultures utilized here, although it likely contributes to CXCL10 induction during the later stages of acute and then chronic HCV infection of the whole liver in vivo. In addition, other IRFs besides IRF3 may bind the proximal ISRE in the CXCL10 promoter, and previous studies have shown that IRF1 and IRF7 bind directly to this site in lung epithelial cells following influenza A virus infection (43). However, it remains unknown whether these IRFs bind chemokine promoters in hepatocytes following HCV infection.