The macrophage antiviral response: Regulation of virus-induced proinflammatory gene expression

Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease characterized by the selective destruction of insulin secreting beta-cells located within pancreatic islets of Langerhans. Viral infection is one environmental factor thought to precipitate the onset of autoimmune diabetes and recent experimental evidence supports a role for macrophages in mediating the destruction of beta-cells following viral infection. Macrophages are thought to participate in the initiating events of IDDM through the production and release of soluble mediators such as interleukin (IL)-1 and nitric oxide; however, the mechanisms by which virus infection activates macrophages have yet to be completely defined. The purpose of this study was to elucidate the mechanisms by which viral infection of macrophages induces the expression of proinflammatory cytokines and antiviral genes. We have identified two signaling pathways that independently regulate macrophage expression of IL-1 and the inducible isoform of nitric oxide synthase (iNOS) in response to viral infection. Virus infection of macrophages induces the expression of IL-1, an event that requires the extracellular signal-regulated kinase (ERK) and the transcription factor PU.1. Additionally, we provide evidence to implicate a novel role for the beta isoform of the calcium-independent phospholipase A2 (iPLA2) in the regulation of virus-induced iNOS expression by macrophages. Interestingly, virus-induced activation of these signaling cascades does not require the classical mediator of host antiviral responses, double-stranded (ds) RNA-dependent protein kinase (PKR). While the mechanism by which viral infection induces ERK and iPLA2 signaling in macrophages remains unclear, the ability of empty virions to activate macrophages is consistent with a role for virus interaction with the cell surface.