COX-2 Induction during Murine Gammaherpesvirus 68 Infection Leads to Enhancement of Viral Gene Expression

Abstract

The gamma subfamily of herpesviruses, including EpsteinBarr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) or human herpesvirus 8 (HHV-8), are associated with tumors and lymphoproliferative disorders (29,43). Murine gammaherpesvirus 68 (MHV-68) is phylogenetically related to EBV and KSHV and provides major research advantages by forming plaques on cell monolayers and establishing productive lytic and latent infections in mice (10,(64)(65)(66). Unlike EBV and KSHV, MHV-68 readily establishes productive infections in many cell culture systems and thus facilitates the examination of gammaherpesvirus replication and de novo infection (66,75,76). This provides an opportunity to examine cellular responses to de novo infection and their role in regulating gammaherpesvirus activity.Prostaglandins (PGs) are potent immunoregulatory lipid mediators generated by arachidonic acid metabolism via two cellular cyclooxygenases, constitutive COX-1 and inducible 22,26,61). PGs are formed by most cell types and exert a variety of actions in various tissues and cells via PG receptors (2,16,19,33,47). PGE 2 is an important proinflammatory prostanoid that mediates many symptoms of inflammation (41,53,56,70). Production of PGE 2 is catalyzed by COX-2, which is induced in response to factors such as bacterial lipopolysaccharides, mitogens, and cytokines (17,31,57,61). However, it is unknown what role the COX-2-PGE 2 pathway might play in responding to gammaherpesvirus de novo infection.Many viruses have been linked to the modulation of COX-2 expression and PG production (9,11,25,44,46,52,60,63,(77)(78)(79). COX-2 is responsible for the exaggerated biosynthesis of PGs under acute inflammatory conditions and in a diverse group of tumors (14,23,32,67). The COX-1 and COX-2 isozymes are the pharmacologic targets of nonsteroidal antiinflammatory drugs (NSAIDs) (26,50,61,71), and NSAIDs that block COX activity and PG production have been recognized as potentially effective antiviral therapeutics (4, 6-8, 51, 62, 73, 79). However, the effect of COX inhibitors on de novo infection of a gammaherpesvirus has not been previously examined. MHV-68 has been used as a model to study the efficacy of other antiviral compounds (3, 48, 49, 68), and we used this system to address the effects of COX-2 inhibition on gammaherpesvirus replication and infection.To enhance our understanding of virus-host cell interactions involved in the replication and pathogenesis of gammaherpesviruses, we examined MHV-68 de novo infection of NIH 3T3 and BHK-21 cells as a model for analyzing the role of PG production and COX-2 activity. We compared the effects of MHV-68 and UV-irradiated MHV-68 infection on COX-2 protein expression and COX-2 promoter activation. COX inhibitors {NS-398 [N-(2-cyclohexyloxy-4-nitrophenyl)-methanesulfonamide] and indomethacin} were tested for their ability to suppress MHV-68 protein expression during de novo infection. Inhibition of protein expression and virion production by NS-398 was relieved in the presence of exogenous PGE 2 ,...

Role of MAPK in the Regulation of Double-Stranded RNA- and Encephalomyocarditis Virus-Induced Cyclooxygenase-2 Expression by Macrophages

“…COX catalyzes the oxidation of arachidonic acid to PGH 2 , which is then isomerized to biologically active eicosanoids and thromboxanes (1). Expression of COX-2 is activated in response to a wide variety of cytokines and inflammatory mediators as well as during virus infection (2)(3)(4)(5)(6)(7). One of the predominate products of COX enzymatic activity is PGE 2 and increased production of this prostaglandin has been shown to modulate the replication and infectivity of a number of viruses (7).…”

Exacerbation of Established Pulmonary Fibrosis in a Murine Model by Gammaherpesvirus

“…To accomplish this, we used a protocol to produce UV light-inactivated gHV68 (UVgHV68), which has previously been shown to limit viral replication (34). Mice were again given FITC intratracheally on Day 0.…”

“…Mock infections were 20 ml of saline. gHV68 was inactivated by exposure to ultraviolet (UV) light using a UV cross-linker set on 120,000 microjoules for four consecutive cycles as previously described (34).…”

Acetylsalicylic acid inhibits hepatitis C virus RNA and protein expression through cyclooxygenase 2 signaling pathways

“…Previous studies have reported that production of COX-2 and PGE 2 modulates replication of human cytomegalovirus, gammaherpesvirus, and hepatitis B virus. [18][19][20] To investigate the possible mechanism(s) responsible for ASA-mediated down-regulation of HCV-RNA expression, we examined COX-2 activity, mRNA, and protein levels in ASAtreated HCV replicon cells. In this study, we found that 4 mM ASA treatment down-regulated COX-2 protein (Fig.…”