Role of IRF4 in IFN-stimulated gene induction and maintenance of Kaposi sarcoma-associated herpesvirus latency in primary effusion lymphoma cells.

[primary effusion lymphoma]

IFN regulatory factor (IRF ) 4 is a hematopoietic cell-specific transcription factor that regulates the maturation and differentiation of immune cells . Using an inducible expression system , we found that IRF 4 directly induced a specific subset of IFN-stimulated genes (ISGs ) in a type I IFN-independent manner in both epithelial and B cell lines . Moreover , Kaposi sarcoma -associated herpesvirus (KSHV )-encoded viral FLICE inhibitory protein (vFLIP ) enhances IRF 4 -mediated gene induction . Coexpression of IRF 4 with vFLIP significantly increased ISG 60 (IFIT 3 ) and Cig 5 (RSAD 2 ) transcription that was dependent on the ability of vFLIP to activate NF-κB . A vFLIP mutant (A 57 L ) defective in NF-κB activation failed to enhance IRF 4 -mediated ISG induction . Thus , we provide a physiologically relevant mechanism by which viral protein-mediated NF-κB activation modulates specific ISG induction by IRF 4 . In contrast , IRF 4 also acted as a negative regulator of KSHV replication and transcription activator expression after induction of KSHV lytic reactivation in KSHV-positive primary effusion lymphoma cells . Taken together , these results suggest a dual role for IRF 4 in regulating ISG induction and KSHV lytic reactivation in primary effusion lymphoma cells .