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1.  Role of IRF4 in IFN-stimulated gene induction and maintenance of KSHV latency in primary effusion lymphoma cells 
Interferon 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 IRF4 directly induced a specific subset of interferon-stimulated genes (ISG) in a type I interferon (IFN)-independent manner in both epithelial and B cell lines. Moreover, Kaposi sarcoma-associated herpesvirus (KSHV)-encoded viral FLICE inhibitory protein (vFLIP) enhances IRF4-mediated gene induction. Co-expression of IRF4 with vFLIP significantly increased ISG60 (IFIT3) and Cig5 (RSAD2) transcription that was dependent on the ability of vFLIP to activate NF-κB. A vFLIP mutant (A57L) – defective in NF-κB activation, failed to enhance IRF4-mediated ISG induction. Thus, we provide a physiologically relevant mechanism where viral protein mediated NF-κB activation modulates specific ISG induction by IRF4. In contrast, IRF4 also acted as a negative regulator of KSHV replication and transcription activator (RTA) expression after induction of KSHV lytic reactivation in KSHV positive primary effusion lymphoma (PEL) cells. Taken together, these results suggest a dual role for IRF4 in regulating ISG induction and KSHV lytic reactivation in PEL cells.
PMCID: PMC3740746  PMID: 23804715
2.  Defective NF-κB signaling in metastatic head and neck cancer cells leads to enhanced apoptosis by dsRNA 
Cancer research  2011;72(1):45-55.
Ligands to several Toll-like receptors (TLR) which mediate innate immune responses and chronic inflammation have been used as adjuvants to immunotherapy to enhance their anti-tumor activity. In particular, double-stranded RNAs that are cognate ligands of TLR3 have been used to trigger pro-apoptotic activity in cancer cells. However, a mechanistic understanding of TLR3-mediated apoptosis and its potential involvement in controlling tumor metastasis has been lacking. In this study we used paired cell lines and fresh tumor specimens, derived from autologous primary and metastatic head and neck squamous cell carcinoma, to investigate the role of TLR3 signaling in metastatic progression. Compared to primary tumor cells, metastatic tumor cells were highly sensitive to TLR3-mediated apoptosis after dsRNA treatment. Enhanced apoptosis in metastatic cells was dependent on dsRNA and TLR3 and also the TLR3 effector signaling protein TRIF. Downstream responses requiring NF-κB were critical for apoptosis in metastatic cells, the defects in which could be resuscitated by alternative pathways of NF-κB activation. By elucidating how TLR3 ligands trigger apoptosis in metastatic cells our findings suggest insights into how to improve their clinical use.
PMCID: PMC3251732  PMID: 22058147
3.  Inhibition of Indoleamine-2,3-dioxygenase (IDO) in Glioblastoma Cells by Oncolytic Herpes Simplex Virus 
Advances in Virology  2012;2012:815465.
Successful oncolytic virus treatment of malignant glioblastoma multiforme depends on widespread tumor-specific lytic virus replication and escape from mitigating innate immune responses to infection. Here we characterize a new HSV vector, JD0G, that is deleted for ICP0 and the joint sequences separating the unique long and short elements of the viral genome. We observed that JD0G replication was enhanced in certain glioblastoma cell lines compared to HEL cells, suggesting that a vector backbone deleted for ICP0 may be useful for treatment of glioblastoma. The innate immune response to virus infection can potentially impede oncolytic vector replication in human tumors. Indoleamine-2,3-dioxygenase (IDO) is expressed in response to interferon γ (IFNγ) and has been linked to both antiviral functions and to the immune escape of tumor cells. We observed that IFNγ treatment of human glioblastoma cells induced the expression of IDO and that this expression was quelled by infection with both wild-type and JD0G viruses. The role of IDO in inhibiting virus replication and the connection of this protein to the escape of tumor cells from immune surveillance suggest that IDO downregulation by HSV infection may enhance the oncolytic activity of vectors such as JD0G.
PMCID: PMC3424635  PMID: 22924042

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